Nancy Raitano Lee

Anatomical Brain Magnetic Resonance Imaging of Typically Developing Children and Adolescents.

Many psychiatric disorders, including some with adult onset such as schizophrenia, are increasingly being conceptualized as stemming from anomalies of neurodevelopment. To explore neurodevelopmental hypotheses of illness, it is useful to have well-characterized data regarding typical maturation to serve as a “yardstick” from which to assess possible deviations. Studies of typical development, and the influences on that development, may also unveil the timing and mechanisms of brain maturation guiding the way for novel interventions. In this overview, we will touch on methodological issues relevant to magnetic resonance imaging (MRI) studies of brain anatomy, summarize MRI findings of neuroanatomic changes during childhood and adolescence, and discuss possible influences on brain development trajectories. As indicated in the previous articles of this series, one of the first steps in measuring brain morphometric characteristics in a conventional anatomic MRI is to classify (or “segment”) individual voxels (the smallest elements of different MRI signals—usually approximately 1 mL) as corresponding to CSF, white matter (WM), or gray matter (GM). Once categorized by tissue type, various parcellations can be performed to derive volumes at the level of lobes (e.g., frontal, temporal, parietal, occipital); regions defined by gyral, sulcal, or GM, WM, and CSF boundaries (e.g., caudate nucleus); or individual voxels. Segmentation and parcellation of MRIs was originally exclusively done by trained individuals outlining particular regions of interest (frequently abbreviated as ROIs) by hand. Although having a highly trained individual manually identify brain regions is considered the closest thing to a “gold standard” available, the time and anatomic expertise necessary for training raters and performing this type of analysis can be prohibitive. This has motivated many laboratories to develop computer algorithms capable of automatically classifying regions of MRI images as belonging to different tissue types and anatomic regions. The rapid progress in this area has made it feasible to perform the type of large scale studies necessary to capture many of the changes associated with typical and atypical brain development. Automated methods have also opened the door to innovative ways of looking at brain structure, such as analyzing the shape and thickness of the cortical sheet. However, the fidelity of automated methods depends on the clarity of the borders between structures, which in turn is determined by a combination of the anatomy of a particular structure and the quality of the MRI image. For example, the amygdala and hippocampus are difficult for automated methods to separate properly because they represent adjacent GM structures. In cases such as these, hand measurements may still be the best approach, although even human raters may need considerable experience before they can consistently identify the borders of such structures on conventional MRI. The data for this overview are largely derived from 387 typically developing subjects (829 scans) participating in an ongoing longitudinal study at the Child Psychiatry Branch of the National Institute of Mental Health. Begun in 1989 by Markus Kruesi, M.D., and Judith Rapoport, M.D., the study design is for participants aged 3 to 30 years to come to the National Institutes of Health at approximately 2-year intervals for brain imaging, psychological and behavioral assessment, and collection of DNA. The emphasis on this single source is not to devalue the many excellent contributions of other investigators but to provide an integrated account from the world’s largest collection of child and adolescent brain MRI scans with data acquired using uniform screening/assessment batteries, the same scanner, and the same methods of image analyses. We have supplemented with references to studies by other laboratories, although a complete review of the field is beyond the scope of this article.

Prenatal growth in humans and postnatal brain maturation into late adolescence

Prenatal life encompasses a critical phase of human brain development, but neurodevelopmental consequences of normative differences in prenatal growth among full-term pregnancies remain largely uncharted. Here, we combine the power of a within-monozygotic twin study design with longitudinal neuroimaging methods that parse dissociable components of structural brain development between ages 3 and 30 y, to show that subtle variations of the in utero environment, as indexed by mild birth weight (BW) variation within monozygotic pairs, are accompanied by statistically significant (i) differences in postnatal intelligence quotient (IQ) and (ii) alterations of brain anatomy that persist at least into late adolescence. Greater BW within the normal range confers a sustained and generalized increase in brain volume, which in the cortical sheet, is specifically driven by altered surface area rather than cortical thickness. Surface area is maximally sensitive to BW variation within cortical regions implicated in the biology of several mental disorders, the risk for which is modified by normative BW variation. We complement this near-experimental test of prenatal environmental influences on human brain development by replicating anatomical findings in dizygotic twins and unrelated singletons. Thus, using over 1,000 brain scans, across three independent samples, we link subtle differences in prenatal growth, within ranges seen among the majority of human pregnancies, to protracted surface area alterations, that preferentially impact later-maturing associative cortices important for higher cognition. By mapping the sensitivity of postnatal human brain development to prenatal influences, our findings underline the potency of in utero life in shaping postnatal outcomes of neuroscientific and public health importance.

Anatomic Magnetic Resonance Imaging of the Developing Child and Adolescent Brain and Effects of Genetic Variation

Magnetic resonance imaging studies have begun to map effects of genetic variation on trajectories of brain development. Longitudinal studies of children and adolescents demonstrate a general pattern of childhood peaks of gray matter followed by adolescent declines, functional and structural increases in connectivity and integrative processing, and a changing balance between limbic/subcortical and frontal lobe functions, which extends well into young adulthood. Twin studies have demonstrated that genetic factors are responsible for a significant amount of variation in pediatric brain morphometry. Longitudinal studies have shown specific genetic polymorphisms affect rates of cortical changes associated with maturation. Although over-interpretation and premature application of neuroimaging findings for diagnostic purposes remains a risk, converging data from multiple imaging modalities is beginning to elucidate the influences of genetic factors on brain development and implications of maturational changes for cognition, emotion, and behavior.

Screening for autism spectrum disorders in children with down syndrome: population prevalence and screening test characteristics.

Objective: We assessed the prevalence of autism spectrum disorders (ASD) and screening test characteristics in children with Down syndrome. Method: Eligible children born in a defined geographic area between January 1, 1996, and December 31, 2003, were recruited through a population-based birth defects registry and community outreach, then screened with the modified checklist for autism in toddlers or social communication questionnaire, as appropriate. Screen-positive children and a random sample of screen-negative children underwent developmental evaluation. Results: We screened 123 children (27.8% of the birth cohort). Mean age was 73.4 months (range, 31–142). Compared to screen-negative children, screen-positive children had similar sociodemographic characteristics but a lower mean developmental quotient (mean difference: 11.0; 95% confidence interval: 4.8–17.3). Weighted prevalences of autistic disorder and total ASD were 6.4% (95% confidence interval [CI]: 2.6%–11.6%) and 18.2% (95% CI: 9.7%–26.8%), respectively. The estimated minimum ASD prevalence, accounting for unscreened children, is 5.1% (95% CI: 3.3%–7.4%). ASD prevalence increased with greater cognitive impairment. Screening test sensitivity was 87.5% (95% CI: 66.6%–97.7%); specificity was 49.9% (95% CI: 37.0%–61.4%). Conclusion: The prevalence of ASD among children with Down syndrome aged 2 to 11 years is substantially higher than in the general population. The modified checklist for autism in toddlers and social communication questionnaire were highly sensitive in children with Down syndrome but could result in many false positive tests if universal screening were implemented using current algorithms. Research needs include development of specific ASD screening algorithms and improved diagnostic discrimination in children with Down syndrome. Timely identification of these co-occurring diagnoses is essential so appropriate interventions can be provided.

Effects of Sex Chromosome Aneuploidies on Brain Development: Evidence From Neuroimaging Studies

Variation in the number of sex chromosomes is a relatively common genetic condition, affecting as many as 1/400 individuals. The sex chromosome aneuploidies (SCAs) are associated with characteristic behavioral and cognitive phenotypes, although the degree to which specific individuals are affected can fall within a wide range. Understanding the effects of different dosages of sex chromosome genes on brain development may help to understand the basis for functional differences in affected individuals. It may also be informative regarding how sex chromosomes contribute to typical sexual differentiation. Studies of 47,XXY males make up the bulk of the current literature of neuroimaging studies in individuals with supernumerary sex chromosomes, with a few small studies or case reports of the other SCAs. Findings in 47,XXY males typically include decreased gray and white matter volumes, with most pronounced effects in the frontal and temporal lobes. Functional studies have shown evidence of decreased lateralization. Although the hypogonadism typically found in 47,XXY males may contribute to the decreased brain volume, the observation that 47,XXX females also show decreased brain volume in the presence of normal pubertal maturation suggests a possible direct dosage effect of X chromosome genes. Additional X chromosomes, such as in 49,XXXXY males, are associated with more markedly decreased brain volume and increased incidence of white matter hyperintensities. The limited data regarding effects of having two Y chromosomes (47,XYY) do not find significant differences in brain volume, although there are some reports of increased head size.

Distinct Cortical Correlates of Autistic versus Antisocial Traits in a Longitudinal Sample of Typically Developing Youth

In humans, behaviors associated with autism and antisociality, disorders characterized by distinct social impairments, can be viewed as quantitative traits that range from frank impairment to normal variation, as found in the general population. Neuroimaging investigations of autism and antisociality demonstrate diagnostically specific aberrant cortical brain structure. However, little is known about structural brain correlates of social behavior in nonclinical populations. Therefore, we sought to determine whether autistic and antisocial traits exhibit dissociable cortical correlates and whether these associations are stable across development among typically developing youth. Three hundred twenty-three typically developing youth (age at first scan: mean = 10.63, SD = 3.71 years) underwent anatomic magnetic resonance imaging (1–6 scans each; total = 742 scans), and provided ratings of autistic and antisocial traits. Higher autistic trait ratings were associated with thinner cortex most prominently in right superior temporal sulcus while higher antisocial trait ratings were associated with thinner cortex in primarily bilateral anterior prefrontal cortices. There was no interaction with age, indicating that these brain–behavior associations were stable across development. Using assessments of both subclinical autistic and subclinical antisocial traits within a large longitudinal sample of typically developing youth, we demonstrate dissociable neuroanatomic correlations that parallel those found in the frank clinical disorders of autism (e.g., superior temporal cortex) and antisociality (e.g., anterior prefrontal cortex). Moreover, these correlations appear to be established in early childhood and remain fixed into early adulthood. These results support the dimensional view of psychopathology and provide neural signatures that can serve as informative endophenotypes for future genetic studies.

Caregiver Report of Executive Functioning in a Population-Based Sample of Young Children With Down Syndrome

The current study describes everyday executive function (EF) profiles in young children with Down syndrome. Caregivers of children with Down syndrome (n  =  26; chronological ages  =  4-10 years; mental ages  =  2-4 years) completed the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P; G. A. Gioia, K. A. Espy, & P. K. Isquith, 2003 ), a caregiver report measure of everyday/functional EF skills in multiple domains. On the BRIEF-P, elevations were noted on a global EF composite as well as the Working Memory and Plan/Organize scales in particular (relative to norms developed for typically developing children of a similar mental age). These results suggest a specific pattern of EF weaknesses in young children with Down syndrome, consistent with the extant literature that has focused primarily on older individuals who have been tested using laboratory EF tasks.

Profiles of Everyday Executive Functioning in Young Children With Down Syndrome

We investigated executive functioning (EF) in children with Down syndrome (DS; n  =  25) and typically developing (TD) children matched for mental age (MA; n  =  23) using the Behavior Rating Inventory of Executive Function-Preschool. We sought to (1) compare children with DS to a developmentally matched control group, and (2) to characterize the EF profile of children with DS. Across teacher and parent reports, significant deficits in working memory and planning were observed in the DS group. Parents, but not teachers, of children with DS also reported difficulties in inhibitory control relative to the comparison group. Results extend earlier findings regarding EF impairments in children with DS. The complementary role inhibitory control may play in this profile is discussed.

Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: implications for idiopathic language impairment and autism spectrum disorders

BACKGROUND  Supernumerary sex chromosome aneuploidies (X/Y-aneuploidies), the presence of extra X and/or Y chromosomes, are associated with heightened rates of language impairments and social difficulties. However, no single study has examined different language domains and social functioning in the same sample of children with tri-, tetra-, and pentasomy X/Y-aneuploidy. The current research sought to fill this gap in the literature and to examine dosage effects of X and Y chromosomes on language and social functioning. METHODS Participants included 110 youth with X/Y-aneuploidies (32 female) and 52 with typical development (25 female) matched on age (mean ∼12 years; range 4-22) and maternal education. Participants completed the Wechsler intelligence scales, and parents completed the childrens communication checklist-2 and the social responsiveness scale to assess language skills and autistic traits, respectively. RESULTS Both supernumerary X and Y chromosomes were related to depressed structural and pragmatic language skills and increased autistic traits. The addition of a Y chromosome had a disproportionately greater impact on pragmatic language; the addition of one or more X chromosomes had a disproportionately greater impact on structural language. CONCLUSIONS Given that we link extra X chromosomes with structural language impairments and an extra Y chromosome with pragmatic language impairments, X/Y-aneuploidies may provide clues to genetic mechanisms contributing to idiopathic language impairment and autism spectrum disorders.

Executive Function in Young Males with Klinefelter (XXY) Syndrome with and without Comorbid Attention-Deficit/Hyperactivity Disorder

Deficits in executive function (EF) are reported to occur in individuals with Klinefelter syndrome (XXY). The degree of impairment, if any, is variable and the nature of these deficits has not been clearly elucidated in young males. In this report, we (a) examine EF skills using multiple tasks in a non-clinic referred group of youth with XXY, (b) describe the extent of EF weaknesses in XXY when this group is compared with typical males of a similar SES or typical males with similar verbal abilities, and (c) evaluate the contribution of comorbid attention-deficit/hyperactivity disorder (ADHD) to EF skills. The sample included 27 males with XXY (ages 9-25), 27 typically developing age- and vocabulary-matched males, and 22 age- and socioeconomic status-matched males. EF tasks included Verbal Fluency, the Trail Making Test, and the CANTAB Spatial Working Memory and Stockings of Cambridge tasks. Mixed model analysis of variance was used to compare the groups on EF tasks and revealed a main effect of group but no group by task interaction. Overall, the XXY group performed less well than both control groups, but performance did not differ significantly as a function of task. ADHD comorbidity in males with XXY was related to poorer EF skills.