Multimodal classification of extremely preterm and term adolescents using the fusiform gyrus: A machine learning approach.

OBJECTIVE: Extremely preterm birth has been associated with atypical visual and neural processing of faces, as well as differences in gray matter structure in visual processing areas relative to full-term peers. In particular, the right fusiform gyrus, a core visual area involved in face processing, has been shown to have structural and functional differences between preterm and full-term individuals from childhood through early adulthood. The current study used multiple neuroimaging modalities to build a machine learning model based on the right fusiform gyrus to classify extremely preterm birth status. METHOD: Extremely preterm adolescents (n = 20) and full-term peers (n = 24) underwent structural and functional magnetic resonance imaging. Group differences in gray matter density, measured via voxel-based morphometry (VBM), and blood-oxygen level-dependent (BOLD) response to face stimuli were explored within the right fusiform. Using group difference clusters as seed regions, analyses investigating outgoing white matter streamlines, regional homogeneity, and functional connectivity during a face processing task and at rest were conducted. A data driven approach was utilized to determine the most discriminative combination of these features within a linear support vector machine classifier. RESULTS: Group differences in two partially overlapping clusters emerged: one from the VBM analysis showing less density in the extremely preterm cohort and one from BOLD response to faces showing greater activation in the extremely preterm relative to full-term youth. A classifier fit to the data from the cluster identified in the BOLD analysis achieved an accuracy score of 88.64% when BOLD, gray matter density, regional homogeneity, and functional connectivity during the task and at rest were included. A classifier fit to the data from the cluster identified in the VBM analysis achieved an accuracy score of 95.45% when only BOLD, gray matter density, and regional homogeneity were included. CONCLUSION: Consistent with previous findings, we observed neural differences in extremely preterm youth in an area that plays an important role in face processing. Multimodal analyses revealed differences in structure, function, and connectivity that, when taken together, accurately distinguish extremely preterm from full-term born youth. Our findings suggest a compensatory role of the fusiform where less dense gray matter is countered by increased local BOLD signal. Importantly, sub-threshold differences in many modalities within the same region were informative when distinguishing between extremely preterm and full-term youth.

Neurobehavioral morbidity of pediatric mild sleep-disordered breathing and obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea is associated with neurobehavioral dysfunction, but the relationship between disease severity as measured by the apnea-hypopnea index and neurobehavioral morbidity is unclear. The objective of our study is to compare the neurobehavioral morbidity of mild sleep-disordered breathing versus obstructive sleep apnea. METHODS: Children 3-12 years old recruited for mild sleep-disordered breathing (snoring with obstructive apnea-hypopnea index < 3) into the Pediatric Adenotonsillectomy Trial for Snoring were compared to children 5-9 years old recruited for obstructive sleep apnea (obstructive apnea-hypopnea 2-30) into the Childhood Adenotonsillectomy Trial. Baseline demographic, polysomnographic, and neurobehavioral outcomes were compared using univariable and multivariable analysis. RESULTS: The sample included 453 participants with obstructive sleep apnea (median obstructive apnea-hypopnea index 5.7) and 459 participants with mild sleep-disordered breathing (median obstructive apnea-hypopnea index 0.5). By polysomnography, participants with obstructive sleep apnea had poorer sleep efficiency and more arousals. Children with mild sleep-disordered breathing had more abnormal executive function scores (adjusted odds ratio 1.96, 95% CI 1.30-2.94) compared to children with obstructive sleep apnea. There were also elevated Conners scores for inattention (adjusted odds ratio 3.16, CI 1.98-5.02) and hyperactivity (adjusted odds ratio 2.82, CI 1.83-4.34) in children recruited for mild sleep-disordered breathing. CONCLUSIONS: Abnormal executive function, inattention, and hyperactivity were more common in symptomatic children recruited into a trial for mild sleep-disordered breathing compared to children recruited into a trial for obstructive sleep apnea. Young, snoring children with only minimally elevated apnea-hypopnea levels may still be at risk for deficits in executive function and attention. TRIAL REGISTRATION: Pediatric Adenotonsillectomy for Snoring (PATS), NCT02562040; Childhood Adenotonsillectomy Trial (CHAT), NCT00560859.

The influence of sociodemographic factors and response style on caregiver report of infant developmental status.

Caregiver report is the most feasible way to assess early childhood development but is susceptible to the influences of response style and sociodemographic factors. In a sample of 571 caregiver-infant dyads (47.8% female; 48% White), we compared caregiver reports on the Ages and Stages Questionnaire-Third Edition (ASQ-3) with reports on a novel, web-based assessment, PediaTrac™. Ratings on PediaTrac correlated with ratings on the ASQ-3 at all time points (2, 4, 6, and 9 months). Caregiver age, response style, and sociodemographic factors accounted for significant variance on both measures. Developmental reporting of early childhood skills is influenced by caregiver response style and sociodemographic factors. These influences must be considered in order to ensure the accurate identification of infant developmental status.

Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm.

We evaluated the relationship between blood levels of inflammatory and neurotrophic proteins during the first postnatal month in 692 children born before the 28th week of gestation and executive function limitations among those 10-year olds who had an IQ ≥ 70. The measures of dysfunction were Z-scores ≤ -1 on the Differential Ability Scales-II working memory (WM) assessment) (N = 164), the NEPSY-II (A Developmental NEuroPSYchological Assessment-II) Inhibition-Inhibition assessment) (N = 350), the NEPSY-II Inhibition-Switching assessment) (N = 345), as well as a Z-score ≤ -1 on all three assessments (identified as the executive dysfunction composite (N = 104). Increased risks of the executive dysfunction composite associated with high concentrations of inflammatory proteins (IL-8, TNF-α, and ICAM-1) were modulated by high concentrations of neurotrophic proteins. This pattern of modulation by neurotrophins of increased risk associated with inflammation was also seen for the working memory limitation, but only with high concentrations of IL-8 and TNF-α, and the switching limitation, but only with high concentrations of ICAM-1. We infer that among children born extremely preterm, risks of executive function limitations might be explained by perinatal systemic inflammation in the absence of adequate neurotrophic capability.

Decreased functional connectivity in the fronto-parietal network in children with mood disorders compared to children with dyslexia during rest: An fMRI study.

Background: The DSM-5 separates the diagnostic criteria for mood and behavioral disorders. Both types of disorders share neurocognitive deficits of executive function and reading difficulties in childhood. Children with dyslexia also have executive function deficits, revealing a role of executive function circuitry in reading. The aim of the current study is to determine whether there is a significant relationship of functional connectivity within the fronto-parietal and cingulo-opercular cognitive control networks to reading measures for children with mood disorders, behavioral disorders, dyslexia, and healthy controls (HC). Method: Behavioral reading measures of phonological awareness, decoding, and orthography were collected. Resting state fMRI data were collected, preprocessed, and then analyzed for functional connectivity. Differences in the reading measures were tested for significance among the groups. Global efficiency (GE) measures were also tested for correlation with reading measures in 40 children with various disorders and 17 HCs. Results: Significant differences were found between the four groups on all reading measures. Relative to HCs and children with mood disorders or behavior disorders, children with dyslexia as a primary diagnosis scored significantly lower on all three reading measures. Children with mood disorders scored significantly lower than controls on a test of phonological awareness. Phonological awareness deficits correlated with reduced resting state functional connectivity MRI (rsfcMRI) in the cingulo-opercular network for children with dyslexia. A significant difference was also found in fronto-parietal global efficiency in children with mood disorders relative to the other three groups. We also found a significant difference in cingulo-opercular global efficiency in children with mood disorders relative to the Dyslexia and Control groups. However, none of these differences correlate significantly with reading measures. Conclusions/significance: Reading difficulties involve abnormalities in different cognitive control networks in children with dyslexia compared to children with mood disorders. Findings of the current study suggest increased functional connectivity of one cognitive control network may compensate for reduced functional connectivity in the other network in children with mood disorders. These findings provide guidance to clinical professionals for design of interventions tailored for children suffering from reading difficulties originating from different pathologies.

Neuroimaging and social behavior in children after traumatic brain injury: findings from the Social Outcomes of Brain Injury in Kids (SOBIK) study.

BACKGROUND: Neuroimaging studies identified either focal and/or non-specific frontotemporolimbic damage resulting from mild-complicated to severe traumatic brain injury (TBI) in a subset of 12 children 8-12 years of age who were part of the Social Outcomes of Brain Injury in Kids (SOBIK) study. The influence of identifiable damage on social behavior was examined. METHODS: Magnetic resonance imaging was obtained on average 2.5 years post injury wherein cases with distinct abnormalities were selected. Various direct, performance-based measures of cognitive-social-emotional functioning were obtained along with data regarding peer relations and friendships in the classroom. RESULTS: Overall, children with TBI were impaired on tasks of social-emotional processing compared to children with orthopedic injury (OI). Ten of the 12 children with TBI had multiple areas of impaired social-emotional functioning in comparison to OI controls. With regards to friendships, four of the nine children with TBI who had classroom data had no mutual friends, four also received low peer acceptance ratings, and two were perceived by peers as having high levels of rejection/victimization in the classroom. CONCLUSIONS: Children with frontotemporolimbic or diffuse damage demonstrated variable social outcomes from their TBI. Results are discussed in terms of the heterogeneity of TBI-related abnormalities and their relationship to social behavior.

Theory of mind in children with traumatic brain injury.

Theory of mind (ToM) involves thinking about mental states and intentions to understand what other people know and to predict how they will act. We studied ToM in children with traumatic brain injury (TBI) and age- and gender-matched children with orthopedic injuries (OI), using a new three-frame Jack and Jill cartoon task that measures intentional thinking separate from contingent task demands. In the key ToM trials, which required intentional thinking, Jack switched a black ball from one hat to another of a different color, but Jill did not witness the switch; in the otherwise identical non-ToM trials, the switch was witnessed. Overall accuracy was higher in children with OI than in those with TBI. Children with severe TBI showed a larger decline in accuracy on ToM trials, suggesting a specific deficit in ToM among children with severe TBI. Accuracy was significantly higher on trials following errors than on trials following correct responses, suggesting that all groups monitored performance and responded to errors with increased vigilance. TBI is associated with poorer intentional processing in school-age children and adolescents relative to peers with OI; furthermore, children with TBI are challenged specifically by intentional demands, especially when their injury is severe. (JINS, 2012, 19, 1-9).

Academic achievement of adolescents born with extremely low birth weight.

AIM: To assess academic achievement, rates of learning disabilities (LD) and special education in extremely low birth weight (ELBW <1 kg) adolescents relative to normal birth weight (NBW) controls and to identify cognitive weaknesses. METHODS: Compared 181 ELBW adolescents born from 1992 to 1995 (mean age 14.8 years, mean BW 809 g, mean GA 26.4 weeks) and 115 NBW term controls. Measures included tests of IQ, reading and math achievement and executive function. Analyses included ANCOVA and logistic and linear regression. Covariates were sex, race and socioeconomic status. RESULTS: Extremely low birth weight adolescents had significantly lower scores on tests of IQ (87.1 vs. 96.4), achievement (88.6 vs. 95.5 reading; 81.3 vs. 93.2 math) and executive function than the NBW group (all p-values <0.001). ELBW also had higher rates of math LD, 51(50%) vs. 26 (28%), OR (95% CI) = 3.10 (1.65, 5.84), p < 0.001, and need for special education, 88 (49%) vs. 11(10%), OR (95% CI) = 11.78 (5.67, 24.47), p < 0.001. Measures of executive function were related to math independent of IQ. CONCLUSIONS: Extremely low birth weight adolescents born in the 1990s have poorer achievement and higher rates of math LD than NBW peers. The findings suggest a need for more intensive interventions addressing the specific cognitive vulnerabilities in this population.

Relationships among post-concussive symptoms and symptoms of PTSD in children following mild traumatic brain injury.

PRIMARY OBJECTIVE: To investigate the occurrence of post-concussive symptoms (PCS) and symptoms of post-traumatic stress disorder (PTSD) in children following mild traumatic brain injuries (TBI). RESEARCH DESIGN: Longitudinal study comparing the outcomes of mild TBI and orthopaedic injuries (OI) in children aged 8-15. METHODS AND PROCEDURES: One hundred and eighty-six children with mild TBI and 99 with OI were recruited prospectively. Parents rated children's PCS and symptoms of PTSD at 2 weeks, 3 months and 12 months post-injury. One hundred and sixty-seven with mild TBI and 84 with OI completed all assessments. MAIN OUTCOMES AND RESULTS: Controlling for symptoms of PTSD, the mild TBI group demonstrated more PCS than the OI group, although the magnitude of group differences diminished with time. Controlling for PCS, the OI group displayed more symptoms of PTSD than the mild TBI group at baseline, but not thereafter. Symptoms of PTSD and PCS were correlated significantly, but more highly in the OI group than the mild TBI group. CONCLUSIONS: Although PCS and symptoms of PTSD are correlated, children with mild TBI are more distinguishable from children with OI based on PCS than on symptoms of PTSD. The latter symptoms, moreover, do not account for increased PCS following mild TBI in children.

Mild traumatic brain injury and executive functions in school-aged children.

OBJECTIVE: This study sought to examine the effects of mild traumatic brain injury (TBI) on executive functions in school-aged children. PARTICIPANTS AND METHOD: The prospective, longitudinal study involved 8-15 year old children, 186 with mild TBI and 99 with mild orthopaedic injuries (OI). They were administered the Stockings of Cambridge and Spatial Working Memory sub-tests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) approximately 10 days, 3 months and 12 months post-injury. Parents completed the Behavior Rating Inventory of Executive Functions (BRIEF) on each occasion, with ratings at the initial assessment intended to assess pre-morbid functioning retrospectively. RESULTS: On the CANTAB, the groups did not differ on the Stockings of Cambridge and the mild TBI group unexpectedly performed better than the OI group on Spatial Working Memory. On the BRIEF, children with mild TBI showed a marginally significant trend toward more problems than the OI group on the Metacognition Index composite. The only BRIEF sub-scale on which they demonstrated significantly more problems was Organization of Materials. The presence of intracranial abnormalities on MRI was associated with more problems on the BRIEF Organization of Materials sub-scale at 3 months, but other findings were not consistent with hypothesized effects of TBI severity. The CANTAB sub-tests were significant predictors of later ratings on the BRIEF, but accounted for modest variance. DISCUSSION: Children with mild TBI show limited evidence of deficits in executive functions, either cognitively or behaviourally, irrespective of injury characteristics. Cognitive tests of executive functions are modest predictors of ratings of executive functions in everyday life, for children both with and without mild TBI.

Dimensions of early speech sound disorders: A factor analytic study.

UNLABELLED: The goal of this study was to classify children with speech sound disorders (SSD) empirically, using factor analytic techniques. Participants were 3-7-year olds enrolled in speech/language therapy (N = 185). Factor analysis of an extensive battery of speech and language measures provided support for two distinct factors, representing the skill dimensions of articulation/phonology and semantic/syntactic skills. To validate these factors, 38 of the children were followed to school age to re-evaluate speech and language skills and assess reading/spelling achievement. The validity of the two factors was supported by their differential associations with school-age reading and spelling achievement, persistence of SSD, and affection status in family members. A closer relationship of the family member to the proband and male gender predicted higher odds of a disorder. The findings suggest that articulation/phonology and language abilities are at least partially independent in children with SSD and that these constructs have distinct clinical and biological correlates. LEARNING OUTCOMES: The reader will develop knowledge about subtypes of speech sound disorders, understand the relationship between early speech sound disorders and later reading and spelling difficulties, and obtain information concerning familial transmission of speech sound disorders.

Long-term parental and family adaptation following pediatric brain injury.

OBJECTIVE: To determine whether parents of children with traumatic brain injuries (TBI) report increased injury-related burden, distress, and family dysfunction and to examine the effects of attrition on the results. METHODS: Children with severe TBI, moderate TBI, and orthopedic injuries were followed at six time points from baseline to 6 years after injury. Parents completed measures of injury-related burden, psychological distress, and family functioning at each assessment. Mixed model analysis was used to examine long-term changes. RESULTS: Attrition was higher among families in the severe TBI group with lower burden thereby amplifying group differences. The severe TBI group reported higher injury-related burden over time after injury than the other groups. Family functioning was moderated by social resources. Families of children with severe TBI and low resources reporting deteriorating functioning over the follow-up interval. CONCLUSIONS: Although environmental advantages moderate long-term effects on family functioning, families of children with severe TBI experience long-standing injury-related burden.

Longitudinal changes in family outcomes of very low birth weight.

OBJECTIVES: Although children with very low birth weight (VLBW, <1500 g) are at high risk for developmental impairments, we know little about the long-term effects of VLBW on families. This study examined long-term family outcomes and their stability over time. METHODS: Participants were the families of 64 children with <750 g birth weight, 54 with 750-1499 g birth weight, and 66 term-born controls. Family burden and parental distress were assessed annually as part of longitudinal follow-up of the children from mean ages 11-14 years. RESULTS: Family burden and parental distress were higher in the <750 g group than in the term-born group, but differences varied with the child's age and family environment. CONCLUSIONS: The findings document long-term effects of VLBW on families that are moderated by the degree of low birth weight, child's age, and family environment.

Family pedigrees of children with suspected childhood apraxia of speech.

UNLABELLED: Forty-two children (29 boys and 13 girls), ages 3-10 years, were referred from the caseloads of clinical speech-language pathologists for suspected childhood apraxia of speech (CAS). According to results from tests of speech and oral motor skills, 22 children met criteria for CAS, including a severely limited consonant and vowel repertoire, difficulty sequencing syllables, and inconsistent and unusual errors. Family pedigrees for these children were constructed through parent interviews and direct testing of nuclear family members. Familial aggregation for speech-sound and language disorders was demonstrated with 86% reporting at least one nuclear family member affected. Based on parent report, 13 of the 22 children (59%) had at least one affected parent. However, CAS was evident in only two siblings of probands with CAS and two probands with other speech-sound disorders. Based on testing, overall affection rates of speech-sound/language disorders were higher in families of children with CAS than in families of children with other speech-sound disorders. Mothers of children with CAS demonstrated a higher affection rate than mothers of children with other speech-sound disorders. A sex-related threshold model of transmission was also supported with brothers more often affected than sisters for male probands only. If our inclusionary criteria for CAS are valid, these findings support a general verbal trait deficit hypothesis. LEARNING OUTCOMES: (1) As a result of this activity, the participant will understand potential familial risk factors for CAS; (2) will differentiate aggregation for speech-sound and language disorders in families with CAS from families of children who have other speech-sound disorders; (3) will distinguish how familial aggregation differs in families of boys and girls with CAS; (4) will determine how children with CAS differ in severity from those with other speech-sound disorders.

Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading.

Speech-sound disorder (SSD) is a complex behavioral disorder characterized by speech-sound production errors associated with deficits in articulation, phonological processes, and cognitive linguistic processes. SSD is prevalent in childhood and is comorbid with disorders of language, spelling, and reading disability, or dyslexia. Previous research suggests that developmental problems in domains associated with speech and language acquisition place a child at risk for dyslexia. Recent genetic studies have identified several candidate regions for dyslexia, including one on chromosome 3 segregating in a large Finnish pedigree. To explore common genetic influences on SSD and reading, we examined linkage for several quantitative traits to markers in the pericentrometric region of chromosome 3 in 77 families ascertained through a child with SSD. The quantitative scores measured several processes underlying speech-sound production, including phonological memory, phonological representation, articulation, receptive and expressive vocabulary, and reading decoding and comprehension skills. Model-free linkage analysis was followed by identification of sib pairs with linkage and construction of core shared haplotypes. In our multipoint analyses, measures of phonological memory demonstrated the strongest linkage (marker D3S2465, P=5.6 x 10(-5), and marker D3S3716, P=6.8 x 10(-4)). Tests for single-word decoding also demonstrated linkage (real word reading: marker D3S2465, P=.004; nonsense word reading: marker D3S1595, P=.005). The minimum shared haplotype in sib pairs with similar trait values spans 4.9 cM and is bounded by markers D3S3049 and D3S3045. Our results suggest that domains common to SSD and dyslexia are pleiotropically influenced by a putative quantitative trait locus on chromosome 3.