Showing papers by "Liv S. Clasen published in 2012"

Prenatal growth in humans and postnatal brain maturation into late adolescence

Abstract: 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.

Using Multivariate Machine Learning Methods and Structural MRI to Classify Childhood Onset Schizophrenia and Healthy Controls

Abstract: Introduction: Multivariate machine learning methods can be used to classify groups of schizophrenia patients and controls using structural magnetic resonance imaging (MRI). However, machine learning methods to date have not been extended beyond classification and contemporaneously applied in a meaningful way to clinical measures. We hypothesized that brain measures would classify groups, and that increased likelihood of being classified as a patient using regional brain measures would be positively related to illness severity, developmental delays and genetic risk. Methods: Using 74 anatomic brain MRI sub regions and Random Forest, we classified 98 COS patients and 99 age, sex, and ethnicity-matched healthy controls. We also used Random Forest to determine the likelihood of being classified as a schizophrenia patient based on MRI measures. We then explored relationships between brain-based probability of illness and symptoms, premorbid development, and presence of copy number variation associated with schizophrenia. Results: Brain regions jointly classified COS and control groups with 73.7% accuracy. Greater brain-based probability of illness was associated with worse functioning (p= 0.0004) and fewer developmental delays (p=0.02). Presence of copy number variation (CNV) was associated with lower probability of being classified as schizophrenia (p=0.001). The regions that were most important in classifying groups included left temporal lobes, bilateral dorsolateral prefrontal regions, and left medial parietal lobes. Conclusions: Schizophrenia and control groups can be well classified using Random Forest and anatomic brain measures, and brain-based probability of illness has a positive relationship with illness severity and a negative relationship with developmental delays/problems and CNV-based risk.

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

Abstract: 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 non-clinical populations. Therefore, we sought to determine if autistic and antisocial traits exhibit dissociable cortical correlates and whether these associations are stable across development among typically developing youth. 323 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.

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

Abstract: Supernumerary sex chromosome aneuploidies (referred to here as X/Y-aneuploidies), the presence of extra X- and/or Y-chromosomes, occur at a collective rate of ~1/475 births (Nielsen & Wohlert, 1990). Sex chromosome trisomies (e.g., XXX, XXY, XYY) occur most frequently, each with rates of ~1/900 births, while tetra- and pentasomies (e.g., XXXX, XXXXX, XXXY, XXXXY) are considerably rarer, each with rates of ~1/85,000 births or fewer (Linden, Bender, & Robinson, 1995). There is longstanding evidence that children with X/Y-aneuploidies have language-learning difficulties. However, only recently, attention also has been drawn to social difficulties, including autism spectrum disorder (ASD) symptomatology, in these groups (for reviews, see Leggett, Jacobs, Nation, Scerif, & Bishop, 2010; Lee, Lopez, Adeyemi, & Giedd, 2011). Given the close connection between idiopathic language impairments and ASDs and the fact no prior studies have examined language and/or social functioning in children with the X/Y tri-, tetra-, and pentasomies, the current study sought to examine both of these domains of functioning in a sample of children with XXX, XXXX, XXXXX, XYY, XXY, XXXY, and XXXXY and typically developing (TD) controls. In particular, we aimed to evaluate dosage effects of X- and Y-chromosomes on language and social functioning in order to shed light not only on the nature of language and social difficulties in children with X/Y aneuploidies, but also on the possible contributions of the X- and Y-chromosomes to idiopathic language impairments and ASDs. Prospective newborn screening studies of X/Y-aneuploidies (Walzer, Bashir, & Silbert, 1990; Ratcliffe et al., 1982, Bender et al., 1983; Netley & Rovet, 1982) and more recent reports (Bishop et al., 2011; Ross, Zeger, Kushner, Zinn, & Roeltgen, 2009) have noted increased rates of language-based learning disorders, including speech, semantic and syntactic deficits (which we refer to as ‘structural language’ or non-social language deficits) and depressed Verbal IQ scores in XXY and XXX. While these children often have lower nonverbal IQ scores than siblings, significant nonverbal learning difficulties are not commonly reported (Bender, Linden, & Robinson, 1991). For males with an additional Y-chromosome (XYY), cognitive findings are inconsistent. Some prospective studies reported about a one standard deviation decrease in general cognitive functioning (Ratcliffe et al., 1982; Walzer et al., 1990). However, when data were pooled across early studies, no significant depression in overall cognitive abilities was found (Netley, 1986). Nevertheless, more recent research suggests that at a minimum, males with XYY have depressed verbal cognitive and structural language skills relative to TD peers (Bishop et al., 2011; Ross et al., 2009). Research on children with X-chromosome tetra- and pentasomies (XXXX, XXXXX, XXXY, XXXXY) suggests decreases in verbal and nonverbal intellectual abilities with each additional X-chromosome (Linden et al., 1995), such that many of these individuals have cognitive abilities in the borderline to intellectually disabled range (Visootsak, Rosner, Dykens, Tartaglia, & Graham, 2007; though Gropman et al., 2010 suggests that nonverbal cognition is relatively preserved in XXXXY despite profound language deficits). Furthermore, studies suggest significant structural language impairments in these groups (Visootsak et al., 2007), including severe dyspraxia resulting in limited to no speech in XXXXY (Gropman et al., 2010). In summary, there appears to be strong evidence for structural language impairments in X/Y-aneuploidies. However, less is known about pragmatic or more social aspects of language, including discourse, understanding of metaphor and humor, and nonverbal communication. The few studies that have been completed converge in implicating pragmatic language difficulties in X/Y trisomies using standardized (Ross et al., 2009) and experimental cognitive tasks (van Rijn et al., 2007) as well as parent report (Bishop et al., 2011). However, no study has examined pragmatic language skills in X/Y tetra- and pentasomies, or pragmatic language vis-a-vis structural language functioning in any X/Y-aneuploidy. Even less is known about the social phenotype associated with X/Y-aneuploidies. Recent studies suggest that the addition of one X-chromosome in males (XXY) is associated with heightened rates of ASDs and social-cognitive impairments (Bishop et al., 2011; Bruining, Swaab, Kas, & van Engeland, 2009; van Rijn, Swaab, Aleman, & Kahn, 2006). In contrast, reports of females with XXX and males with XXXY and XXXXY are not indicative of increased ASD risk (Bishop et al., 2011; Visootsak et al., 2007). Reports of males with XYY indicate that an additional Y-chromosome may be associated with social difficulties, as these males appear to have increased rates of ASDs and ASD symptomatology (Bishop et al., 2011; Geerts, Steyaert, & Fryns, 2003). Thus, the current research sought to examine verbal and nonverbal intellectual skills, structural and pragmatic language abilities, and ASD symptomatology in a large sample of children with sex chromosome tri-, tetra-, and pentasomies and TD controls in order to examine X- and Y-chromosome dosage effects on these phenotypes. Unlike previous studies investigating genotype-specific profiles, we focused on quantity of supernumerary sex chromosomes. Therefore, we collapsed across genotypes (e.g., +0X=XX, XY; +1X=XXX, XXY), and in the case of tetra- and pentasomies, limited sample size necessitated combining these groups (i.e., +2/3X=XXXX, XXXXX, XXXY, XXXXY; consistent with prior work by Visootsak et al., 2007) in order to answer study questions regarding X and Y dosage effects. We predict that: 1- Increased X- and Y-chromosome number will be associated with increased intellectual impairments with a discrepantly stronger impact on verbal relative to nonverbal intelligence. 2-Supernumerary X- and Y-chromosomes will be associated with impairments in both structural and pragmatic language; however, a supernumerary Y-chromosome will be associated with more pronounced pragmatic than structural language deficits. 3-Elevated ASD symptomatology will be associated with X/Y-aneuploidy, but supernumerary X-chromosome dosage effects will not be present.

Autism risk gene MET variation and cortical thickness in typically developing children and adolescents.

Abstract: MET receptor tyrosine kinase (MET) has been proposed as a candidate risk gene for autism spectrum disorder (ASD) based on associations between MET polymorphisms and ASD diagnosis, as well as evidence from animal studies that MET protein may regulate early development of cortical regions implicated in the neurobiology of ASD. The relevance of differences in MET signaling for human cortical development remains unexamined, however. We sought to address this issue by relating genotype at a functional single nucleotide polymorphism within the MET promoter (rs1858830, G→C), to in vivo measures of cortical thickness development derived from 222 healthy children and adolescents with 514 longitudinally acquired structural MRI brain scans between ages 9 and 22 years. We identified a statistically significant, developmentally fixed, and stepwise CT reduction with increasing C allele dose in superior and middle temporal gyri, ventral pre- and post-central gyri, and anterior cingulate bilaterally, and in the right fronto-polar cortex. We were also able to demonstrate that mean CT within these cortical regions showed a statistically significant reduction with increasing scores on a continuous measure of autistic traits (the Social Responsiveness Scale). The cortical regions highlighted by our analyses are not only established areas of MET expression during prenatal life, but are also key components of the “social brain” which have frequently shown structural and functional abnormalities in autism. Our results suggest that genetic differences in the MET gene may influence the development of cortical systems implicated in the neurobiology of ASD

Delayed White Matter Growth Trajectory in Young Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia

Abstract: CONTEXT Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. OBJECTIVE To study WM growth differences in nonpsychotic siblings of patients with COS. DESIGN Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. SETTING National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). INTERVENTION Magnetic resonance imaging. MAIN OUTCOME MEASURE White matter growth rates. RESULTS We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. CONCLUSIONS In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.

Allelic Variation Within the Putative Autism Spectrum Disorder Risk Gene Homeobox A1 and Cerebellar Maturation in Typically Developing Children and Adolescents

Abstract: LAY ABSTRACT—Autism is known to be highly heritable, and has been associated with abnormalities in the development of several brain structures, including the cerebellum. Previous research has hinted that a gene controlling the development of posterior brain regions such as the cerebellum, may influence risk for autism. This gene is called Homeobox Domain A1 (HOXA1), and the variant within HOXA1 that has been most studied in relation to autism (A218G) falls within a gene region that is important for HOXA1 protein functioning. Although we know that autism appear to influence the dynamics of brain development, and that cerebellar anatomy continues to change over the lifespan – we do not know if A218G genotype influences cerebellar development over time. We studied this issue in typically developing controls who had a total of 296 repeat structural brain scans taken between ages 5 and 23 years of age. The volume of multiple cerebellar components was measures by hand in each scan, and we related developmental changes in these volumes to A218G genotype. We found that, in a part of the cerebellum implicated in autism, A218G genotype modified the rate of cerebellar growth. This suggests for the first time that the putative ASD risk gene HOXA1 has the capacity to modify the longitudinal development of cerebellar systems implicated in ASD neurobiology. SCIENTIFIC ABSTRACT—Homeobox-A-1 (HOXA1) has been proposed as a candidate gene for autism spectrum disorder (ASD) as it regulates embryological patterning of hind-brain structures implicated in autism neurobiology. In line with this notion, a non-synonymous single nucleotide polymorphism within a highly conserved domain of HOXA1 - A218G (rs10951154) has been linked to both ASD risk, and cross-sectional differences in superior posterior lobar cerebellar anatomy in late adulthood. Despite evidence for early onset and developmentally dynamic cerebellar involvement in ASD, little is known of the relationship between A218G genotype and maturation of the cerebellum over early development. We addressed this issue using 296 longitudinally acquired structural magnetic resonance imaging brain scans from 116 healthy individuals between 5 and 23 years of age. Mixed models were used to compare the relationship between age and semi-automated measures of cerebellar volume in A-homozygotes (AA) and carriers of the G allele (Gcar). Total cerebellar volume increased between ages 5 and 23 years in both groups. However, this was accelerated in the Gcar relative to the AA group (Genotype-byage interaction term, p=0.03), and driven by genotype-dependent differences in the rate of bilateral

Reply to Segal: Are relationships between birth weight and intelligence quotient variation within twin pairs modulated by patterns of handedness discordance?

Abstract: We are grateful for Professor Segal’s interesting letter (1), prompting us to delve deeper into a question that was nested within, but not directly addressed by our recent article (2): Are relationships between birth weight (BW) and intelligence quotient (IQ) variation within twin pairs modulated by patterns of handedness discordance? In a sample of 67 monozygotic (MZ) twin pairs (of which ∼40% pairs were discordant for handedness), Professor Segal had found that lower IQ most often segregated with lower BW in handedness-discordant twin pairs when the left-handed member had the lower BW (3). This finding was argued to support two theoretical accounts for reported associations between twinning and left-handedness: the accompaniment of left-handedness by BW reduction relative to the right-handed cotwin [discordant left lighter (HDll)] indexing consequences of prenatal compromise, and left-handedness without BW reduction relative to the cotwin [discordant left heavier (HDlh)] potentially indexing the alternative mechanism of “delayed zygotic splitting and disrupted asymmetry determination” in twins.