Amy L. Conrad

Biological and Environmental Predictors of Behavioral Sequelae in Children Born Preterm

OBJECTIVE: By using behavioral outcome measures of children who were born preterm, we evaluated differences between children who were born at term and children who were born at extremely low (ELBW; <1000 g) and very low birth weights (VLBW; 1000–1499 g) and assessed the relationship of birth weight, socioeconomic status, and cognitive ability to behavioral outcome. METHODS: We studied a total of 104 children (aged 7–16 years). Of these, 49 had a preterm birth (31 of ELBW and 18 of VLBW). The remaining 55 were healthy control subjects. Children were administered tests of cognitive ability. Parents and teachers completed behavioral assessments. Multivariate analyses of covariance assessed differences between children who were born at term and those who were born of ELBW and of VLBW on behavioral measures. Hierarchical linear regressions were used to assess relationships among biological (birth weight), environmental (socioeconomic status), intellectual, and behavioral variables. RESULTS: Children who were born at term had fewer parent reports of hyperactivity/inattention and depression/anxiety symptoms than children of ELBW and VLBW. Teacher ratings were not significant between groups. Birth weight was consistently the strongest predictor of parent ratings of behavioral outcome, and intelligence level did not seem to mediate this relationship. CONCLUSIONS: Negative behavioral sequelae of preterm birth remain significant in middle childhood and adolescence, although the contribution of multiple factors to neurobehavioral outcome is complex. Research to assess these relationships, integrated with anatomic and functional neuroimaging, is needed to advance knowledge and improve outcomes for children who are born preterm.

Long-term outcome of brain structure in premature infants: effects of liberal vs restricted red blood cell transfusions.

OBJECTIVE To assess the long-term outcome of brain structure in preterm infants, at an average age of 12 years, who received a red blood cell transfusion for anemia of prematurity. DESIGN As neonates, this cohort of infants participated in a clinical trial in which they received red blood cell transfusions based on a high pretransfusion hematocrit threshold (liberal group) or a low hematocrit threshold (restricted group). These 2 preterm groups were compared with a group of full-term healthy control children. SETTING Tertiary care hospital. PARTICIPANTS Magnetic resonance imaging scans for 44 of the original 100 subjects were obtained. INTERVENTION Liberal vs restricted transfusion. MAIN OUTCOME MEASURES Intracranial volume, total brain tissue, total cerebrospinal fluid, cerebral cortex and cerebral white matter volume, subcortical nuclei volume, and cerebellum volume. RESULTS Intracranial volume was substantially smaller in the liberal group compared with controls. Intracranial volume in the restricted group was not different from controls. Whole-cortex volume was not different in either preterm group compared with controls. Cerebral white matter was substantially reduced in both preterm groups, more so for the liberal group. The subcortical nuclei were substantially decreased in volume, equally so for both preterm groups compared with controls. When sex effects were evaluated, the girls in the liberal group had the most significant abnormalities. CONCLUSION Red blood cell transfusions affected the long-term outcome of premature infants as indicated by reduced brain volumes at 12 years of age for neonates who received transfusions using liberal guidelines.

Neuropsychological, behavioral, and academic sequelae of cleft: early developmental, school age, and adolescent/young adult outcomes.

This article reviews behavioral, neuropsychological, and academic outcomes of individuals with cleft across three age levels: (1) infancy/early development, (2) school age, and (3) adolescence/young adulthood. The review points out that attachment, neurocognitive functioning, academic performance/learning, and adjustment outcomes are the result of a complex interaction between biological and environmental factors and vary with developmental level, sex, and craniofacial anomaly diagnosis. The degree to which associated genetic or neurodevelopmental conditions may explain inconsistent findings is unknown and suggests the need for caution in generalizing from group data on cleft.

Neuropsychological Functioning in Children with Non-Syndromic Cleft of the Lip and/or Palate

Objective: Evaluate neuropsychological functioning in children with non-syndromic cleft of the lip and/or palate (NSCL/P) through profile variance within type of cleft and comparisons to controls. Methods: Children ages 7 to 17 years participated; 66 had a diagnosis of NSCL/P and 87 were healthy controls. Neuropsychological tests of language, visual-perceptual, executive functioning, and memory skills were administered. Between- and within-group differences were assessed. Results: Within cleft types, children with NSCLP had an even profile with equal Verbal and Performance IQ (VIQ and PIQ, respectively). Children with non-syndromic cleft palate only (NSCP) had significantly lower VIQ than PIQ, while children with non-syndromic cleft lip only (NSCL) showed a nonsignificant trend for higher VIQ than PIQ. Overall, subjects with NSCL/P performed lower on measures of expressive language and verbal memory than controls. Conclusions: While deficits in verbal and memory skills for children with NSCL/P remain apparent, there is still uncertainty around the possible influence of cleft type on the pattern of deficits.

Cerebellum structure differences and relationship to speech in boys and girls with nonsyndromic cleft of the lip and/or palate.

Objective To identify regional cerebellar structural differences in boys and girls with nonsyndromic cleft of the lip and/or palate and determine whether these differences are related to speech impairment. Design Between 2003 and 2007, measures on cerebellar volume were obtained on 43 children with nonsyndromic cleft of the lip and/or palate and 43 age- and sex-matched, healthy controls. Children with the cleft condition also received speech evaluations. Children with nonsyndromic cleft of the lip and/or palate were recruited from clinic records, and controls (screened for medical, psychiatric, speech/language, and behavioral concerns) were recruited from the local community. All tests were administered at a large midwestern hospital. Boys and girls with nonsyndromic cleft of the lip and/or palate were compared with the healthy controls on global and regional measures of cerebellar volume. Areas of significant difference were then correlated with measures of speech to assess relationships in children with nonsyndromic cleft of the lip and/or palate. Results Boys with nonsyndromic cleft of the lip and/or palate had smaller cerebellums than controls (p = .002); whereas, for girls, only regional reductions in size reached significance (corpus medullare, p = .040). Cerebellum size was correlated with articulation for boys (p = .045). Conclusions These findings lend support to previous research documenting abnormal brain structure in children with nonsyndromic cleft of the lip and/or palate and suggest that the cerebellum may play a role in speech deficits along with other structural causes, at least in boys.

Hyperactivity, impulsivity, and inattention in boys with cleft lip and palate: relationship to ventromedial prefrontal cortex morphology

The purpose of this study is to evaluate quantitative structural measures of the ventromedial prefrontal cortex (vmPFC) in boys with isolated clefts of the lip and/or palate (ICLP) relative to a comparison group and to associate measures of brain structure with quantitative measures of hyperactivity, impulsivity, and inattentiveness. A total of 50 boys with ICLP were compared to 60 healthy boys without clefts. Magnetic resonance imaging brain scans were used to evaluate vmPFC structure. Parents and teachers provided quantitative measures of hyperactivity, impulsivity, and inattentiveness using the Pediatric Behavior Scale. Boys with ICLP had significantly higher ratings of hyperactivity/impulsivity/inattention (HII) and significantly increased volume of the right vmPFC relative to the comparison group. There was a direct relationship between HII score and vmPFC volume in both the ICLP group and control group, but the relationship was in the opposite direction: in ICLP, the higher the vmPFC volume, the higher the HII score; for the comparison group, the lower the vmPFC volume, the greater the HII score. The vmPFC is a region of the brain that governs behaviors of hyperactivity, impulsivity and inattention (HII). In boys with ICLP, there are higher levels of HII compared to the controls and this is directly related to a significantly enlarged volume of the right vmPFC. Enlargement of this region of the brain is therefore considered to be pathological in the ICLP group and supports the notion that abnormal brain structure (from abnormal brain development) is the underlying etiology for the abnormal behaviors seen in this population.

Reading in subjects with an oral cleft: speech, hearing and neuropsychological skills.

OBJECTIVE To evaluate speech, hearing, and neuropsychological correlates to reading among children, adolescents, and young adults with nonsyndromic cleft of the lip and/or palate (NSCL/P). METHOD All testing was completed in a single visit at a Midwestern university hospital. Subjects in both the NSCL/P (n = 80) and the control groups (n = 62) ranged in age from 7-26 years (average age = 17.60 and 17.66, respectively). Subjects completed a battery of standardized tests evaluating intelligence, neuropsychological skills, and word reading. Subjects with NSCL/P also underwent speech assessment, and past audiology records were evaluated. RESULTS After controlling for age and socioeconomic status, subjects with cleft performed significantly worse on a test of word reading. For subjects with cleft, word reading deficits were not associated with measures of speech or hearing, but were correlated with impairments in auditory memory. CONCLUSION These findings show poorer reading among subjects with NSCL/P compared with those without. Further work needs to focus on correlates of reading among subjects with cleft to allow early identification and appropriate intervention/accommodation for those at risk.

Sex differences in parietal lobe structure and development.

Structural magnetic resonance imaging studies provide evidence for sex differences in the human brain. Differences in surface area and the proportion of gray to white matter volume are observed, in particular in the parietal lobe. To our knowledge, no studies have examined sex differences in parietal lobe structure in younger populations or in the context of development. The present study evaluated sex differences in the structure of the parietal lobe in children aged 7 to 17 years. In addition, by adding a cohort of previously studied adults aged 18 to 50 years, sex differences in parietal lobe structure were examined across the age span of 7 to 50 years. Compared with the adult sample, the younger sample showed that the ratio of parietal lobe cortex to white matter was greater in female brains, but no sex differences in surface area. When examining the effects of age, surface area exhibited a significant sex-age interaction. In male brains, there was essentially no decrease in surfaces area over time, whereas in female brains, there was a significant decrease in surface area over time. These findings support the notion of structural sex differences in the parietal lobe, not only in the context of cross-sectional assessment but also in terms of differences in developmental trajectories.

Altered Brain Function, Structure, and Developmental Trajectory in Children Born Late Preterm

Background:Late preterm birth (34–36 wk gestation) is a common occurrence with potential for altered brain development.Methods:This observational cohort study compared children at age 6–13 y based on the presence or absence of the historical risk factor of late preterm birth. Children completed a battery of cognitive assessments and underwent magnetic resonance imaging of the brain.Results:Late preterm children (n = 52) demonstrated slower processing speed (P = 0.035) and scored more poorly in visual-spatial perception (P = 0.032) and memory (P = 0.007) than full-term children (n = 74). Parents of late preterm children reported more behavioral difficulty (P = 0.004). There were no group differences in cognitive ability or academic achievement. Imaging revealed similar intracranial volumes but less total tissue and more cerebrospinal fluid (P = 0.004) for late preterm children compared to full-term children. The tissue difference was driven by differences in the cerebrum (P = 0.028) and distributed across cortical (P = 0.051) and subcortical tissue (P = 0.047). Late preterm children had a relatively smaller thalamus (P = 0.012) than full-term children. Only full-term children demonstrated significant decreases in cortical tissue volume (P < 0.001) and thickness (P < 0.001) with age.Conclusion:Late preterm birth may affect cognition, behavior, and brain structure well beyond infancy.

Effects of Unilateral Clefts on Brain Structure

OBJECTIVE To evaluate potential abnormalities in brain structure of children and adolescents with unilateral clefts. DESIGN Case-control study. SETTING Tertiary care center. PARTICIPANTS Boys aged 7 to 17 years with right (n=14) and left (n=19) clefts were compared with healthy age-matched boys (n=57). MAIN EXPOSURES Structural brain measures were obtained using magnetic resonance imaging. OUTCOME MEASURE It was explored whether laterality of clefts had a significant effect on brain structure. To this end, volumes of tissue types and various brain regions were evaluated. RESULTS Total white matter was significantly lower in boys with right clefts compared with boys with left clefts and healthy boys. Gross regional analyses demonstrated that reductions in white matter were evident in both the cerebellum and the cerebrum in boys with right clefts. Furthermore, within the cerebrum, white matter volumes were particularly low in the frontal lobes and the occipital lobes. CONCLUSIONS These preliminary results suggest that right clefts may be associated with more abnormalities in brain structure. More generally, laterality of a birth defect may have a significant effect on a developing organism.