Language At Rest: A Longitudinal Study Of Intrinsic Functional Connectivity In Preterm Children

Preterm (PT) children show early cognitive and language deficits and display altered cortical connectivity for language compared to term (T) children. Developmentally, functional connectivity networks become more segregated and integrated through the weakening of short-range and strengthening of long-range connections. The specific aims of this study are: (1) To use residual fMRI data to investigate intrinsic connectivity development from ages 8 to 16 years in PT vs. T controls; and (2) To correlate intrinsic connectivity to cognitive and language scores. Longitudinal intrinsic connectivity distribution (ICD) values were assessed in PT (n = 13) compared to T children (n = 12) at ages 8 vs. 16 years using a Linear Mixed Effects model. Connectivity values in regions generated by the group x age interaction analysis were correlated with scores on full IQ (FSIQ), verbal IQ (VIQ), verbal comprehension IQ (VCIQ), performance IQ (PIQ), Peabody Picture Vocabulary Test­Revised (PPVT­R), and Rapid Naming Composite (RDRL_cmp). The group x age analysis revealed significant ICD differences in the following regions: bilateral Brodmann area (BA) 47­BA11­BA10­L BA45 (p=0.0002) and L fusiform­BA18­BA19 (p=0.008). The larger frontal region (bilateral BA47-BA11-BA10-L BA45) was separated into subregions for further analysis, which showed the following significant ICD group x age differences: L and R BA47 (p=0.03 and p=0.0006, respectively), bilateral BA11 (p=0.0008), L and R BA10 (p=0.0005 and 0.005, respectively), and L BA46 (p=0.03). Over time, PT ICD increased in: bilateral BA47­BA11­BA10­L BA45 (p\u3c0.0001), L and R BA47 (p=0.02 and \u3c0.0001, respectively), bilateral BA11 (p\u3c0.0001), L and R BA10 (p\u3c0.0001 for both), and L BA46 (p=0.002). In addition, PT showed decreased ICD in L fusiform­BA18­BA19 (p=0.002). In contrast, the T subjects had no significant changes in ICD values over time. At age 16, PT had greater ICD than T in: bilateral BA47­BA11­BA10­L BA45 (p=0.0002), L & R BA47 (p=0.03 & p=0.0007), bilateral BA11 (p=0.0009), L & R BA10 (p=0.0006 & p=0.005), and L BA46 (p=0.03). PT had less ICD than T in L fusiform­BA18­BA19 (p=0.04). L fusiform­BA18­BA19 ICD positively correlated to scores on VIQ (p=0.021), PIQ (p=0.041), and FSIQ (p=0.015). None of the other regions correlated to scores on the cognitive tasks. The L fusiform-BA18-BA19 region includes the visual word form area, which has long been associated with reading performance and complex visual processing. These data demonstrate for the first time that, over the course of adolescence, prematurely-born children undergo widespread developmental changes in intrinsic connectivity that differ from term-born children. The development of resting state connectivity in prematurely-born children does not reflect compensatory alterations but rather appears to underscore and perpetuate impairment in language and cognitive processing

Absence of neural speech discrimination in preterm infants at term-equivalent age

Children born preterm are at higher risk to develop language deficits. Auditory speech discrimination deficits may be early signs for language developmental problems. The present study used functional near-infrared spectroscopy to investigate neural speech discrimination in 15 preterm infants at term-equivalent age compared to 15 full term neonates. The full term group revealed a significantly greater hemodynamic response to forward compared to backward speech within the left hemisphere extending from superior temporal to inferior parietal and middle and inferior frontal areas. In contrast, the preterm group did not show differences in their hemodynamic responses during forward versus backward speech, thus, they did not discriminate speech from non-speech. Groups differed significantly in their responses to forward speech, whereas they did not differ in their responses to backward speech. The significant differences between groups point to an altered development of the functional network underlying language acquisition in preterm infants as early as in term-equivalent age

Alterations in functional connectivity for language in prematurely born adolescents

Recent data suggest recovery of language systems but persistent structural abnormalities in the prematurely born. We tested the hypothesis that subjects who were born prematurely develop alternative networks for processing language. Subjects who were born prematurely (n = 22; 600–1250 g birth weight), without neonatal brain injury on neonatal cranial ultrasound, and 26 term control subjects were examined with a functional magnetic resonance imaging (fMRI) semantic association task, the Wechsler Intelligence Scale for Children-III (WISC-III) and the Clinical Evaluation of Language Fundamentals (CELF). In-magnet task accuracy and response times were calculated, and fMRI data were evaluated for the effect of group on blood oxygen level dependent (BOLD) activation, the correlation between task accuracy and activation and the functional connectivity between regions activating to task. Although there were differences in verbal IQ and CELF scores between the preterm (PT) and term control groups, there were no significant differences for either accuracy or response time for the in-magnet task. Both groups activated classic semantic processing areas including the left superior and middle temporal gyri and inferior frontal gyrus, and there was no significant difference in activation patterns between groups. Clear differences between the groups were observed in the correlation between task accuracy and activation to task at P < 0.01, corrected for multiple comparisons. Left inferior frontal gyrus correlated with accuracy only for term controls and left sensory motor areas correlated with accuracy only for PT subjects. Left middle temporal gyri correlated with task accuracy for both groups. Connectivity analyses at P < 0.001 revealed the importance of a circuit between left middle temporal gyri and inferior frontal gyrus for both groups. In addition, the PT subjects evidenced greater connectivity between traditional language areas and sensory motor areas but significantly fewer correlated areas within the frontal lobes when compared to term controls. We conclude that at 12 years of age, children born prematurely and children born at term had no difference in performance on a simple lexical semantic processing task and activated similar areas. Connectivity analyses, however, suggested that PT subjects rely upon different neural pathways for lexical semantic processing when compared to term controls. Plasticity in network connections may provide the substrate for improving language skills in the prematurely born

Language Network Function in Young Children Born Very Preterm

Language deficits are reported in preterm born children across development. Recent neuroimaging studies have found functional alterations in large-scale brain networks underlying these language deficits, but the early childhood development of the language network has not been investigated. Here, we compared intrinsic language network connectivity in 4-year-old children born VPT and term-born controls, using defined language regions (Broca’s area, Wernicke’s areas, and their homologues in the right hemisphere). Resting-state functional magnetic resonance imaging (fMRI) was obtained, and the group differences in whole-brain connectivity were examined from each seed as well as correlations with language outcomes. We found significantly decreased functional connectivity in almost all language regions in children born VPT compared to their term controls. Notably, Broca’s area homologue in the right hemisphere emerged as a functional hub of decreased connectivity in VPT group, specifically to bilateral inferior frontal and supramarginal gyri; connectivity strength between Broca’s area homologue with the right supramarginal and the left inferior frontal gyri was associated with better language outcomes at 4 years of age. Wernicke’s area and its homologue also showed decreased inter-hemispheric connections to bilateral supramarginal gyri in the VPT group. Decreased intra- and inter-hemispheric connectivity among primary language regions suggests immature and altered function in the language network in children born VPT

Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR childre

Neonatal feeding skills in preterm infants and the relationship to speech and expressive language skills at approximately ten years of age

This study sought to determine whether neonatal feeding skills in extremely preterm infants (EPT) had an association with scores on speech and expressive language measures at approximately ten years of age. Additionally, neonatal feeding abilities were analyzed to determine if there was an association with sensorimotor and visuomotor test measures at approximately ten years of age. Eighty-four EPT children were categorized based on feeding history at 34 weeks gestational age into two groups: infants who were primarily oral feeding (POF), and infants who were primarily tube feeding (PTF). There was no significant difference in size or sex between the two groups. Independent t-tests with a chi-square analysis were used to analyze the composition of the two groups. The majority of infants in the PTF group were characteristically white, had lower birth weights, and a history of bronochopulmonary dysplasia (BPD). Only the variable of race, however, withstood statistical analysis for multiple t-tests. One-way ANOVA procedures determined that there was no significant difference between the performance of the two feeding groups on standardized measures of speech or oral expression at 10 years of age. The parent perceptions of the children’s speech and oral expression skills also did not differ between the two groups. Additionally, one feeding group did not perform better than the other on measures of sensorimotor or visuomotor skills. While no association was determined in the current study, results remained inconclusive and warrant further investigation with a greater variety of standardized measures of speech, oral expression, and sensorimotor and visuomotor skill

Interhemispheric temporal lobe connectivity predicts language impairment in adolescents born preterm.

Although language difficulties are common in children born prematurely, robust neuroanatomical correlates of these impairments remain to be established. This study investigated whether the greater prevalence of language problems in preterm (versus term-born) children might reflect injury to major intra- or interhemispheric white matter pathways connecting frontal and temporal language regions. To investigate this, we performed a comprehensive assessment of language and academic abilities in a group of adolescents born prematurely, some of whom had evidence of brain injury at birth (n = 50, mean age: 16 years, mean gestational age: 27 weeks) and compared them to a term-born control group (n = 30). Detailed structural magnetic resonance imaging and diffusion-tractography analyses of intrahemispheric and interhemispheric white matter bundles were performed. Analysis of intrahemispheric pathways included the arcuate fasciculus (dorsal language pathway) and uncinate fasciculus/extreme capsule (ventral language pathway). Analysis of interhemispheric pathways (in particular, connections between the temporal lobes) included the two major commissural bundles: the corpus callosum and anterior commissure. We found language impairment in 38% of adolescents born preterm. Language impairment was not related to abnormalities of the arcuate fasciculus (or its subsegments), but was associated with bilateral volume reductions in the ventral language pathway. However, the most significant volume reduction was detected in the posterior corpus callosum (splenium), which contains interhemispheric connections between the occipital, parietal and temporal lobes. Diffusion tractography showed that of the three groups of interhemispheric fibres within the splenium, only those connecting the temporal lobes were reduced. Crucially, we found that language impairment was only detectable if the anterior commissure (a second temporal lobe commissural pathway) was also small. Regression analyses showed that a combination of anatomical measures of temporal interhemispheric connectivity (through the splenium of the corpus callosum and anterior commissure) explained 57% of the variance in language abilities. This supports recent theories emphasizing the importance of interhemispheric connections for language, particularly in the developing brain

Évaluation électrophysiologique auditive et examen du langage et de l’attention chez l’enfant né prématurément et l’enfant né à terme

L’objectif de cette thèse est l’étude du développement de l’attention auditive et des capacités de discrimination langagière chez l’enfant né prématurément ou à terme. Les derniers mois de grossesse sont particulièrement importants pour le développement cérébral de l’enfant et les conséquences d’une naissance prématurée sur le développement peuvent être considérables. Les enfants nés prématurément sont plus à risque de développer une variété de troubles neurodéveloppementaux que les enfants nés à terme. Même en l’absence de dommages cérébraux visibles, de nombreux enfants nés avant terme sont à risque de présenter des troubles tels que des retards langagiers ou des difficultés attentionnelles. Dans cette thèse, nous proposons donc une méthode d’investigation des processus préattentionnels auditifs et de discrimination langagière, à l’aide de l’électrophysiologie à haute densité et des potentiels évoqués auditifs (PEAs). Deux études ont été réalisées. La première visait à mettre sur pied un protocole d’évaluation de l’attention auditive et de la discrimination langagière chez l’enfant en santé, couvrant différents stades de développement (3 à 7 ans, 8 à 13 ans, adultes ; N = 40). Pour ce faire, nous avons analysé la composante de Mismatch Negativity (MMN) évoquée par la présentation de sons verbaux (syllabes /Ba/ et /Da/) et non verbaux (tons synthétisés, Ba : 1578 Hz/2800 Hz ; Da : 1788 Hz/2932 Hz). Les résultats ont révélé des patrons d’activation distincts en fonction de l’âge et du type de stimulus présenté. Chez tous les groupes d’âge, la présentation des stimuli non verbaux a évoqué une MMN de plus grande amplitude et de latence plus rapide que la présentation des stimuli verbaux. De plus, en réponse aux stimuli verbaux, les deux groupes d’enfants (3 à 7 ans, 8 à 13 ans) ont démontré une MMN de latence plus tardive que celle mesurée dans le groupe d’adultes. En revanche, en réponse aux stimuli non verbaux, seulement le groupe d’enfants de 3 à 7 ans a démontré une MMN de latence plus tardive que le groupe d’adulte. Les processus de discrimination verbaux semblent donc se développer plus tardivement dans l’enfance que les processus de discrimination non verbaux. Dans la deuxième étude, nous visions à d’identifier les marqueurs prédictifs de déficits attentionnels et langagiers pouvant découler d’une naissance prématurée à l’aide des PEAs et de la MMN. Nous avons utilisé le même protocole auprès de 74 enfants âgés de 3, 12 et 36 mois, nés prématurément (avant 34 semaines de gestation) ou nés à terme (au moins 37 semaines de gestation). Les résultats ont révélé que les enfants nés prématurément de tous les âges démontraient un délai significatif dans la latence de la réponse MMN et de la P150 par rapport aux enfants nés à terme lors de la présentation des sons verbaux. De plus, les latences plus tardives de la MMN et de la P150 étaient également corrélées à des performances langagières plus faibles lors d’une évaluation neurodéveloppementale. Toutefois, aucune différence n’a été observée entre les enfants nés à terme ou prématurément lors de la discrimination des stimuli non verbaux, suggérant des capacités préattentionnelles auditives préservées chez les enfants prématurés. Dans l’ensemble, les résultats de cette thèse indiquent que les processus préattentionnels auditifs se développent plus tôt dans l'enfance que ceux associés à la discrimination langagière. Les réseaux neuronaux impliqués dans la discrimination verbale sont encore immatures à la fin de l'enfance. De plus, ceux-ci semblent être particulièrement vulnérables aux impacts physiologiques liés à la prématurité. L’utilisation des PEAs et de la MMN en réponse aux stimuli verbaux en bas âge peut fournir des marqueurs prédictifs des difficultés langagières fréquemment observées chez l’enfant prématuré.The aim of this thesis is to investigate early auditory attention and language development in full-term and preterm children. The last months of pregnancy are particularly important for the child’s cerebral development, and the impacts of a premature birth on his/her neurodevelopment can be substantial. Prematurely born children are at higher risk of developing a variety of neurodevelopmental disorders compared to full-terms. Even without visible brain injury, many premature children are at risk of presenting disorders such as language delays and attentional difficulties. In this thesis, we suggest an approach to investigate pre-attentional processes and early language discrimination abilities in infants using high-density electrophysiology and auditory event-related potentials (AERPs). We conducted two studies. The first one aimed at establishing a paradigm to evaluate auditory attention and language discrimination development in healthy full-term children, over different developmental stages (3 to 7 years, 8 to 13 years, adults; N = 40). To do so, we analyzed the Mismatch Negativity (MMN) component in response to speech (spoken syllables /Ba/ and /Da/) and non-speech stimuli (frequency-synthesized tones, Ba: 1578 Hz/2800 Hz; Da: 1788 Hz/2932 Hz). Distinct patterns of activation were revealed according to stimulus type and age. In all groups, non-speech stimuli elicited an MMN of larger amplitude and earlier latency than did the presentation of speech stimuli. Moreover, in response to speech stimuli, both children groups (3 to 7 years, 8 to 13 years) showed a significantly delayed MMN response compared to the adults group. In contrast, in response to non-speech stimuli, only the youngest group (3 to 7 years) showed a significantly delayed MMN compared to the adults. Age-related differences for tone discrimination therefore appear to occur earlier in children’s development than do the discriminative processes for speech sounds. In the second study, we aimed at identifying the electrophysiological markers of auditory attention and language deficits often incurred by a premature birth. We thus presented this paradigm to 74 infants born preterm (before 34 gestational weeks) or full-term (at least 37 gestational weeks), aged 3, 12 and 36 months old. Our results indicated that preterm children of all age groups showed a significantly delayed MMN and P150 responses to speech stimuli compared to full-terms. Moreover, significant correlations were found between the delayed MMN and P150 responses to speech sounds and lower language scores on a neurodevelopmental assessment. However, no significant differences were found between full-term and preterm children for the MMN in response to non-speech stimuli, suggesting preserved pre-attentional auditory discrimination abilities in these children. Altogether, the findings from this thesis indicate that the neurodevelopmental processes associated with auditory pre-attentional skills occur earlier in childhood compared to language discrimination processes. Cerebral networks involved in speech discrimination are still immature in late childhood. Furthermore, neural networks involved in speech discrimination and language development also appear to be particularly vulnerable to the impacts of prematurity. The use of AERPs and the MMN response to speech stimuli in infancy can thus provide predictive markers of language difficulties commonly seen in premature infants

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth