Dede Greenstein

Intellectual ability and cortical development in children and adolescents

Children who are adept at any one of the three academic ‘Rs (reading, writing and arithmetic) tend to be good at the others, and grow into adults who are similarly skilled at diverse intellectually demanding activities. Determining the neuroanatomical correlates of this relatively stable individual trait of general intelligence has proved difficult, particularly in the rapidly developing brains of children and adolescents. Here we demonstrate that the trajectory of change in the thickness of the cerebral cortex, rather than cortical thickness itself, is most closely related to level of intelligence. Using a longitudinal design, we find a marked developmental shift from a predominantly negative correlation between intelligence and cortical thickness in early childhood to a positive correlation in late childhood and beyond. Additionally, level of intelligence is associated with the trajectory of cortical development, primarily in frontal regions implicated in the maturation of intelligent activity. More intelligent children demonstrate a particularly plastic cortex, with an initial accelerated and prolonged phase of cortical increase, which yields to equally vigorous cortical thinning by early adolescence. This study indicates that the neuroanatomical expression of intelligence in children is dynamic.

Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation.

There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from a delay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory of each cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developing controls (log rank test χ(1)2 = 5,609, P < 1.0 × 10−20). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported.

How Does Your Cortex Grow

Understanding human cortical maturation is a central goal for developmental neuroscience. Significant advances toward this goal have come from two recent strands of in vivo structural magnetic resonance imaging research: (1) longitudinal study designs have revealed that factors such as sex, cognitive ability, and disease are often better related to variations in the tempo of anatomical change than to variations in anatomy at any one time point; (2) largely cross-sectional applications of new surface-based morphometry (SBM) methods have shown how the traditional focus on cortical volume (CV) can obscure information about the two evolutionarily and genetically distinct determinants of CV: cortical thickness (CT) and surface area (SA). Here, by combining these two strategies for the first time and applying SBM in >1250 longitudinally acquired brain scans from 647 healthy individuals aged 3–30 years, we deconstruct cortical development to reveal that distinct trajectories of anatomical change are hidden within, and give rise to, a curvilinear pattern of CV maturation. Developmental changes in CV emerge through the sexually dimorphic and age-dependent interaction of changes in CT and SA. Moreover, SA change itself actually reflects complex interactions between brain size-related changes in exposed cortical convex hull area, and changes in the degree of cortical gyrification, which again vary by age and sex. Knowing of these developmental dissociations, and further specifying their timing and sex-biases, provides potent new research targets for basic and clinical neuroscience.

Puberty-related influences on brain development

Puberty is a time of striking changes in cognition and behavior. To indirectly assess the effects of puberty-related influences on the underlying neuroanatomy of these behavioral changes we will review and synthesize neuroimaging data from typically developing children and adolescents and from those with anomalous hormone or sex chromosome profiles. The trajectories (size by age) of brain morphometry differ between boys and girls, with girls generally reaching peak gray matter thickness 1-2 years earlier than boys. Both boys and girls with congenital adrenal hyperplasia (characterized by high levels of intrauterine testosterone), have smaller amygdala volume but the brain morphometry of girls with CAH did not otherwise significantly differ from controls. Subjects with XXY have gray matter reductions in the insula, temporal gyri, amygdala, hippocampus, and cingulate-areas consistent with the language-based learning difficulties common in this group.

Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence

Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating “movies” of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with “masculinization” of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.

Identification of Genetically Mediated Cortical Networks: A Multivariate Study of Pediatric Twins and Siblings

Structural magnetic resonance imaging data from 308 twins, 64 singleton siblings of twins, and 228 singletons were analyzed using structural equation modeling and selected multivariate methods to identify genetically mediated intracortical associations. Principal components analyses (PCA) of the genetic correlation matrix indicated a single factor accounting for over 60% of the genetic variability in cortical thickness. When covaried for mean global cortical thickness, PCA, cluster analyses, and graph models identified genetically mediated fronto-parietal and occipital networks. Graph theoretical models suggest that the observed genetically mediated relationships follow small world architectural rules. These findings are largely concordant with other multivariate studies of brain structure and function, the twin literature, and current understanding on the role of genes in cortical neurodevelopment.

Imaging Neuroinflammation in Alzheimer's Disease with Radiolabeled Arachidonic Acid and PET

Incorporation coefficients (K*) of arachidonic acid (AA) in the brain are increased in a rat model of neuroinflammation, as are other markers of AA metabolism. Data also indicate that neuroinflammation contributes to Alzheimers disease (AD). On the basis of these observations, K* for AA was hypothesized to be elevated in patients with AD. Methods: A total of 8 patients with AD with an average (±SD) Mini-Mental State Examination score of 14.7 ± 8.4 (mean age, 71.7 ± 11.2 y) and 9 controls with a normal Mini-Mental State Examination score (mean age, 68.7 ± 5.6 y) were studied. Each subject received a 15O-water PET scan of regional cerebral blood flow, followed after 15 min by a 1-11C-AA scan of regional K* for AA. Results: In the patients with AD, compared with control subjects, global gray matter K* for AA (corrected or uncorrected for the partial-volume error [PVE]) was significantly elevated, whereas only PVE-uncorrected global cerebral blood flow was reduced significantly (P < 0.05). A false-discovery-rate procedure indicated that PVE-corrected K* for AA was increased in 78 of 90 identified hemispheric gray matter regions. PVE-corrected regional cerebral blood flow, although decreased in 12 regions at P < 0.01 by an unpaired t test, did not survive the false-discovery-rate procedure. The surviving K* increments were widespread in the neocortex but were absent in caudate, pallidum, and thalamic regions. Conclusion: These preliminary results show that K* for AA is widely elevated in the AD brain, particularly in regions reported to have high densities of senile (neuritic) plaques with activated microglia. To the extent that the elevations represent upregulated AA metabolism associated with neuroinflammation, PET with 1-11C-AA could be used to examine neuroinflammation in patients with AD and other brain diseases.

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories.

Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P=0.009–0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

Compared to what? Early brain overgrowth in autism and the perils of population norms.

BACKGROUND Early brain overgrowth (EBO) in autism spectrum disorder (ASD) is among the best replicated biological associations in psychiatry. Most positive reports have compared head circumference (HC) in ASD (an excellent proxy for early brain size) with well-known reference norms. We sought to reappraise evidence for the EBO hypothesis given 1) the recent proliferation of longitudinal HC studies in ASD, and 2) emerging reports that several of the reference norms used to define EBO in ASD may be biased toward detecting HC overgrowth in contemporary samples of healthy children. METHODS Systematic review of all published HC studies in children with ASD. Comparison of 330 longitudinally gathered HC measures between birth and 18 months from male children with autism (n = 35) and typically developing control subjects (n = 22). RESULTS In systematic review, comparisons with locally recruited control subjects were significantly less likely to identify EBO in ASD than norm-based studies (p < .001). Through systematic review and analysis of new data, we replicate seminal reports of EBO in ASD relative to classical HC norms but show that this overgrowth relative to norms is mimicked by patterns of HC growth age in a large contemporary community-based sample of US children (n ~ 75,000). Controlling for known HC norm biases leaves inconsistent support for a subtle, later emerging and subgroup specific pattern of EBO in clinically ascertained ASD versus community control subjects. CONCLUSIONS The best-replicated aspects of EBO reflect generalizable HC norm biases rather than disease-specific biomarkers. The potential HC norm biases we detail are not specific to ASD research but apply throughout clinical and academic medicine.

Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): An update†

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention‐deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109–125; Faraone et al., 2005; Biol Psychiatry 57:1313–1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275‐R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431–434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7‐repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow‐up (n = 107, baseline mean age n = 9, follow‐up mean age of n = 15) prompted reexamination of this gene. The DRD4 7‐repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7‐repeat allele was associated with better cognitive performance (measured by the WISC‐III) (P = 0.013–0.07) as well as a trend for association with better long‐term outcome. This provides further evidence of the role of the DRD4 7‐repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder.