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1.  The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository 
NeuroImage  2015;124(0 0):1149-1154.
The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING Portal and filing a Data Use Agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal.
doi:10.1016/j.neuroimage.2015.04.057
PMCID: PMC4628902  PMID: 25937488
2.  Anxiety is related to indices of cortical maturation in typically developing children and adolescents 
Brain structure & function  2015;221(6):3013-3025.
Anxiety is a risk factor for many adverse neuropsychiatric and socioeconomic outcomes, and has been linked to functional and structural changes in the ventromedial prefrontal cortex (VMPFC). However, the nature of these differences, as well as how they develop in children and adolescents, remains poorly understood. More effective interventions to minimize the negative consequences of anxiety require better understanding of its neurobiology in children. Recent research suggests that structural imaging studies may benefit from clearly delineating between cortical surface area and thickness when examining these associations, as these distinct cortical phenotypes are influenced by different cellular mechanisms and genetic factors. The present study examined relationships between cortical surface area and thickness of the VMPFC and a self-report measure of anxiety (SCARED-R) in 287 youths aged 7–20 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Age and gender interactions were examined for significant associations in order to test for developmental differences. Cortical surface area and thickness were also examined simultaneously to determine whether they contribute independently to the prediction of anxiety. Anxiety was negatively associated with relative cortical surface area of the VMPFC as well as with global cortical thickness, but these associations diminished with age. The two cortical phenotypes contributed additively to the prediction of anxiety. These findings suggest that higher anxiety in children may be characterized by both delayed expansion of the VMPFC and an altered trajectory of global cortical thinning. Further longitudinal studies will be needed to confirm these findings.
doi:10.1007/s00429-015-1085-9
PMCID: PMC5064818  PMID: 26183468
Anxiety; Brain development; Cortical surface area; Cortical thickness; Magnetic resonance imaging; Ventromedial prefrontal cortex
3.  Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults 
NeuroImage : Clinical  2016;13:188-200.
One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21–25 years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non-users of cannabis. These participants have been followed longitudinally since age 7–9.9 years as part of a large multi-site longitudinal study of ADHD, the Multimodal Treatment Study of Children with ADHD (MTA). We examined task-independent intrinsic functional connectivity (iFC) within 9 functional networks using a 2 × 2 design, which compared four groups of participants: (1) individuals with a childhood diagnosis of ADHD who currently use cannabis (n = 23); (2) individuals with ADHD who do not currently use cannabis (n = 22); (3) comparisons who currently use cannabis (n = 15); and (4) comparisons who do not currently use cannabis (n = 15). The main effects of childhood ADHD were primarily weakened iFC in networks supporting executive function and somatomotor control. Contrary to expectations, effects of cannabis use were distinct from those of diagnostic group and no interactions were observed. Exploratory brain-behavior analyses suggested that ADHD-related effects were primarily linked with poorer neurocognitive performance. Deficits in the integrity of functional networks supporting executive function and somatomotor control are consistent with the phenotypic and neurocognitive features of ADHD. Our data suggest that cannabis use does not exacerbate ADHD-related alterations, but this finding awaits replication in a larger sample. Longitudinal neuroimaging studies are urgently required to delineate the neurodevelopmental cascade that culminates in positive and negative outcomes for those diagnosed with ADHD in childhood.
Highlights
•Alterations in functional organization persist in those with childhood ADHD.•Network alterations can be linked with specific aspects of the ADHD phenotype.•Cannabis use does not appear to exacerbate ADHD-related alterations.•Longitudinal studies are required to capture the long-term impact of cannabis use.
doi:10.1016/j.nicl.2016.09.012
PMCID: PMC5153452  PMID: 27995073
ADHD; Cannabis; Marijuana; fMRI; Functional connectivity; Neurocognitive
4.  Conservation of Distinct Genetically-Mediated Human Cortical Pattern 
PLoS Genetics  2016;12(7):e1006143.
The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10−3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets.
Author Summary
Although functional and anatomical connections among cortical regions have been intensively explored, genetically-mediated relationships between cortical regions have not been pursued to the same degree. Identifying genetic factors that mediate these relationships among different brain subcomponents can provide insight into how the human brain is organized and functions. We have assessed the genetic relationships among cortical regions using an integrated approach that considers twin data, genotype information among a large set of unrelated individuals, and gene expression measurements from postmortem neural tissues. We looked for evidence that subsets of cortical brain regions are under common or unique genetic control. We found that the patterns of genetic relationships are highly consistent across three independent data sets and multiple lines of evidence, suggesting that the patterning of cortical surface area is strongly mediated by genetic factors and, furthermore, likely reflects underlying anatomical and possibly functional relationships among cortical brain regions.
doi:10.1371/journal.pgen.1006143
PMCID: PMC4961377  PMID: 27459196
6.  Dyslexia and language impairment associated genetic markers influence cortical thickness and white matter in typically developing children 
Brain imaging and behavior  2016;10(1):272-282.
Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.
doi:10.1007/s11682-015-9392-6
PMCID: PMC4639472  PMID: 25953057
Dyslexia; Language impairment; KIAA0319; DYX3; DYX2; Imaging-genetics
7.  Microstructural asymmetry of the corticospinal tracts predicts right–left differences in circle drawing skill in right-handed adolescents 
Brain Structure & Function  2016;221(9):4475-4489.
Most humans show a strong preference to use their right hand, but strong preference for the right hand does not necessarily imply a strong right–left asymmetry in manual proficiency (i.e., dexterity). Here we tested the hypothesis that intra-individual asymmetry of manual proficiency would be reflected in microstructural differences between the right and left corticospinal tract (CST) in a cohort of 52 right-handed typically-developing adolescents (11–16 years). Participants were asked to fluently draw superimposed circles with their right dominant and left non-dominant hand. Temporal regularity of circle drawing movements was assessed for each hand using a digitizing tablet. Although all participants were right-handed, there was substantial inter-individual variation regarding the relative right-hand advantage for fluent circle drawing. All subjects underwent whole-brain diffusion tensor imaging at 3 Tesla. The right and left CST were defined as regions-of-interest and mean fractional anisotropy (FA) and diffusivity values were calculated for right and left CST. On average, mean FA values were higher in the left CST relative to right CST. The degree of right–left FA asymmetry showed a linear relationship with right–left asymmetry in fluent circle drawing after correction for age and gender. The higher the mean FA values were in the left dominant CST relative to the right non-dominant CST, the stronger was the relative right-hand advantage for regular circle drawing. These findings show that right–left differences in manual proficiency are highly variable in right-handed adolescents and that this variation is associated with a right-left microstructural asymmetry of the CST.
doi:10.1007/s00429-015-1178-5
PMCID: PMC5102955  PMID: 26754837
Manual dexterity; Brain development; Circle drawing; Corticospinal tract; Hemispheric asymmetry; Diffusion tensor imaging
8.  Family Income, Parental Education and Brain Structure in Children and Adolescents 
Nature neuroscience  2015;18(5):773-778.
Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. Here, we investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1099 typically developing individuals between 3 and 20 years. Income was logarithmically associated with brain surface area. Specifically, among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data indicate that income relates most strongly to brain structure among the most disadvantaged children. Potential implications are discussed.
doi:10.1038/nn.3983
PMCID: PMC4414816  PMID: 25821911
9.  Large-scale genomics unveil polygenic architecture of human cortical surface area 
Nature Communications  2015;6:7549.
Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2∼0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N=466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.
How genetic variation contributes to brain morphology is still poorly understood. Here Chen et al. combine brain imaging with single-nucleotide polymorphism data to discover that a substantial degree of cortical variation is derived from underlying genetic differences.
doi:10.1038/ncomms8549
PMCID: PMC4518289  PMID: 26189703
10.  Brain Volume Reductions in Adolescent Heavy Drinkers 
Background
Brain abnormalities in adolescent heavy drinkers may result from alcohol exposure, or stem from pre-existing neural features.
Method
This longitudinal morphometric study investigated 40 healthy adolescents, ages 12–17 at study entry, half of whom (n=20) initiated heavy drinking over the 3 year follow-up. Both assessments included high-resolution magnetic resonance imaging. FreeSurfer was used to segment brain volumes, which were measured longitudinally using the newly developed QUARC tool.
Results
At baseline, participants who later transitioned into heavy drinking showed smaller left cingulate, pars triangularis, and rostral anterior cingulate volume, and less right cerebellar white matter volumes (p<.05), compared to continuous non-using teens. Over time, participants who initiated heavy drinking showed significantly greater volume reduction in the left ventral diencephalon, left inferior and middle temporal gyrus, and left caudate and brain stem, compared to substance-naïve youth (p<.05).
Conclusion
Findings suggest preexisting volume differences in frontal brain regions in future drinkers and greater brain volume reduction in subcortical and temporal regions after alcohol use was initiated. This is consistent with literature showing pre-existing cognitive deficits on tasks recruited by frontal regions, as well as post-drinking consequences on brain regions involved in language and spatial tasks.
doi:10.1016/j.dcn.2014.02.005
PMCID: PMC4061267  PMID: 24632141
adolescence; alcohol abuse; brain development; neuroimaging; magnetic resonance imaging
11.  HIV-Associated Distal Neuropathic Pain is Associated with Smaller Total Cerebral Cortical Gray Matter 
Journal of neurovirology  2014;20(3):209-218.
Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.
doi:10.1007/s13365-014-0236-8
PMCID: PMC4040150  PMID: 24549970
HIV Distal Neuropathic Pain; Structural MRI; Cortical Volume
12.  Dyslexia and language impairment associated genetic markers influence cortical thickness and white matter in typically developing children 
Brain Imaging and Behavior  2015;10:272-282.
Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11682-015-9392-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11682-015-9392-6
PMCID: PMC4639472  PMID: 25953057
Dyslexia; Language impairment; KIAA0319; DYX3; DYX2; Imaging-genetics
13.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
doi:10.1093/arclin/acu009
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
14.  Genome-Wide Association Study of Shared Components of Reading Disability and Language Impairment 
Genes, brain, and behavior  2013;12(8):792-801.
Written and verbal language are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits—specifically reading disability (RD) and language impairment (LI)—are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic, and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR=1.81, p=5.45 × 10−7) and COL4A2 (OR=1.71, p=7.59×10−7). Markers within NDST4 showed the strongest associations with LI individually (OR=1.827, p=1.40×10−7). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (p=0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.
doi:10.1111/gbb.12085
PMCID: PMC3904347  PMID: 24024963
ALSPAC; Language Impairment; Reading Disability; Dyslexia GWAS; ZNF385D; PING
15.  The Challenge of Connecting the Dots in the B.R.A.I.N 
Neuron  2013;80(2):10.1016/j.neuron.2013.09.008.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts, and discuss likely technological deliverables and neuroscience progress.
doi:10.1016/j.neuron.2013.09.008
PMCID: PMC3864648  PMID: 24139032
16.  Early Adolescent Cortical Thinning Is Related to Better Neuropsychological Performance 
Adolescence is characterized by significant neuromaturation, including extensive cortical thinning, particularly in frontal regions. The goal of this study was to examine the behavioral correlates of neurostructural development in early adolescence. Participants were 185 healthy 12- to 14-year-olds (44% female) recruited from local schools. Participants completed a comprehensive neuropsychological test battery and magnetic resonance imaging session. Cortical surface reconstruction and thickness estimates were performed via FreeSurfer. Age and cortical thickness were negatively correlated in 10 brain regions, 7 of which were in frontal areas (β = −.15 to −.25, ps ≤.05). Hierarchical linear regressions examined the influence of cortical thickness on working memory, attention, verbal learning and memory, visuospatial functioning, spatial planning and problem solving, and inhibition, controlling for age and intracranial volume. Thinner parietal cortices predicted better performances on tests of verbal learning and memory, visuospatial functioning, and spatial planning and problem solving (β = −.14 to −.24, ps ≤.05). Age, spanning from 12 to 14 years, accounted for up to 6% of cortical thickness, suggesting substantial thinning during early adolescence, with males showing more accelerated thinning than females between ages 12 and 14. For both males and females, thinner parietal association cortices corresponded with better neurocognitive functioning above and beyond age alone.
doi:10.1017/S1355617713000878
PMCID: PMC3791607  PMID: 23947395
Adolescence; Cortical thickness; FreeSurfer; Neurocognitive testing; Neuropsychology; Normal development
17.  Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection 
Journal of neurovirology  2013;19(4):393-401.
MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T-cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79% initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T-cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.
doi:10.1007/s13365-013-0185-7
PMCID: PMC3776609  PMID: 23838849
Antiretroviral therapy; brain; CD4+ T-cell; immune recovery/reconstitution; inflammation; MRI
18.  Salivary Cortisol and Prefrontal Cortical Thickness in Middle-Aged Men: A Twin Study 
NeuroImage  2010;53(3):1093-1102.
Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51–59 years old. Small but significant negative phenotypic associations were found between cortisol levels and the thickness of left dorsolateral (superior frontal gyrus, left rostral middle frontal gyrus) and ventrolateral (pars opercularis, pars triangularis, pars orbitalis) prefrontal regions, and right dorsolateral (superior frontal gyrus) and medial orbital frontal cortex. Most of the associations remained significant after adjusting for general cognitive ability, cardiovascular risk factors, and depression. Bivariate genetic analyses suggested that some of the associations were primarily accounted for by shared genetic influences; that is, some of the genes that tend to result in increased cortisol levels also tend to result in reduced prefrontal cortical thickness. Aging has been associated with reduced efficiency of hypothalamic-pituitary-adrenal function, with frontal lobe shrinkage, and with increases in health problems, but our present data do not allow us to determine the direction of effects. Moreover, the degree or the direction of the observed associations and the extent of their shared genetic underpinnings may well change as these individuals age. Longitudinal assessments are underway to elucidate the direction of the associations and the genetic underpinnings of longitudinal phenotypes for changes in cortisol and brain morphology.
doi:10.1016/j.neuroimage.2010.02.026
PMCID: PMC4034538  PMID: 20156572
heritability; magnetic resonance imaging (MRI); hippocampus; HPA axis structure; genetic correlation
19.  PhenX RISING: real world implementation and sharing of PhenX measures 
BMC Medical Genomics  2014;7:16.
Background
The purpose of this manuscript is to describe the PhenX RISING network and the site experiences in the implementation of PhenX measures into ongoing population-based genomic studies.
Methods
Eighty PhenX measures were implemented across the seven PhenX RISING groups, thirty-three of which were used at more than two sites, allowing for cross-site collaboration. Each site used between four and 37 individual measures and five of the sites are validating the PhenX measures through comparison with other study measures. Self-administered and computer-based administration modes are being evaluated at several sites which required changes to the original PhenX Toolkit protocols. A network-wide data use agreement was developed to facilitate data sharing and collaboration.
Results
PhenX Toolkit measures have been collected for more than 17,000 participants across the PhenX RISING network. The process of implementation provided information that was used to improve the PhenX Toolkit. The Toolkit was revised to allow researchers to select self- or interviewer administration when creating the data collection worksheets and ranges of specimens necessary to run biological assays has been added to the Toolkit.
Conclusions
The PhenX RISING network has demonstrated that the PhenX Toolkit measures can be implemented successfully in ongoing genomic studies. The next step will be to conduct gene/environment studies.
doi:10.1186/1755-8794-7-16
PMCID: PMC3994539  PMID: 24650325
PhenX; Phenotype; Epidemiology; Risk factors; Harmonization
20.  The NIH Toolbox Cognition Battery: Results from a Large Normative Developmental Sample (PING) 
Neuropsychology  2013;28(1):1-10.
Objective
The NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance.
Method
The NTCB was administered to a sample of 1020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States.
Results
General additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores.
Conclusions
The results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors.
doi:10.1037/neu0000001
PMCID: PMC3925365  PMID: 24219608
Computerized Assessment; Cognitive Development; Socioeconomic Status
21.  A web-portal for interactive data exploration, visualization, and hypothesis testing 
Clinical research studies generate data that need to be shared and statistically analyzed by their participating institutions. The distributed nature of research and the different domains involved present major challenges to data sharing, exploration, and visualization. The Data Portal infrastructure was developed to support ongoing research in the areas of neurocognition, imaging, and genetics. Researchers benefit from the integration of data sources across domains, the explicit representation of knowledge from domain experts, and user interfaces providing convenient access to project specific data resources and algorithms. The system provides an interactive approach to statistical analysis, data mining, and hypothesis testing over the lifetime of a study and fulfills a mandate of public sharing by integrating data sharing into a system built for active data exploration. The web-based platform removes barriers for research and supports the ongoing exploration of data.
doi:10.3389/fninf.2014.00025
PMCID: PMC3972454  PMID: 24723882
data exploration; data sharing; genetics; data dictionary; imaging; hypothesis testing
22.  Brain development during the preschool years 
Neuropsychology review  2012;22(4):313-333.
The preschool years represent a time of expansive psychological growth, with the initial expression of many psychological abilities that will continue to be refined into young adulthood. Likewise, brain development during this age is characterized by its “blossoming” nature, showing some of its most dynamic and elaborative anatomical and physiological changes. In this article, we review human brain development during the preschool years, sampling scientific evidence from a variety of sources. First, we cover neurobiological foundations of early postnatal development, explaining some of the primary mechanisms seen at a larger scale within neuroimaging studies. Next, we review evidence from both structural and functional imaging studies, which now accounts for a large portion of our current understanding of typical brain development. Within anatomical imaging, we focus on studies of developing brain morphology and tissue properties, including diffusivity of white matter fiber tracts. We also present new data on changes during the preschool years in cortical area, thickness, and volume. Physiological brain development is then reviewed, touching on influential results from several different functional imaging and recording modalities in the preschool and early school-age years, including positron emission tomography (PET), electroencephalography (EEG) and event-related potentials (ERP), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS). Here, more space is devoted to explaining some of the key methodological factors that are required for interpretation. We end with a section on multimodal and multidimensional imaging approaches, which we believe will be critical for increasing our understanding of brain development and its relationship to cognitive and behavioral growth in the preschool years and beyond.
doi:10.1007/s11065-012-9214-1
PMCID: PMC3511633  PMID: 23007644
23.  Caudate Volume Predicts Neurocognitive Performance in Youth with Heavy Prenatal Alcohol Exposure 
Background
Fetal alcohol spectrum disorders (FASD) result from heavy prenatal alcohol exposure, and are characterized, in some cases, by CNS anomalies and cognitive impairment. Regional patterns of neuroanatomical abnormalities suggest that alcohol exerts selective damage on the developing fetal brain. This study assessed brain-behavior relationships in a sample of youth with histories of heavy prenatal alcohol exposure. The aim was to characterize how structural brain alterations observed in our previous studies relate to cognitive deficits commonly reported in individuals with histories of heavy prenatal alcohol exposure.
Methods
Twenty-one youth (mean age 13 years) with histories of heavy prenatal alcohol exposure and seven non-exposed healthy comparison subjects underwent structural magnetic resonance imaging (MRI) and neurobehavioral testing. Regional brain volumes within the alcohol-exposed group were correlated with neuropsychological measures of cognitive control and verbal learning/recall, as these aspects of cognition have previously been shown to be vulnerable to alcohol teratogenesis.
Results
Between-group effect sizes revealed moderate to large cognitive performance and brain volume decrements in alcohol-exposed subjects, compared to typically developing peers. Within the alcohol-exposed group, volume of the caudate nuclei was the most consistent predictor of neuropsychological performance, after controlling for potentially confounding variables including total brain volume, IQ, and age.
Conclusions
These data are consistent with previous research associating gestational alcohol exposure with structural and functional changes of the caudate nucleus. Our findings extend this previous work by demonstrating that volume reductions of the caudate have behavioral relevance for this population, in relation to cognitive control and verbal learning and recall abilities.
doi:10.1111/j.1530-0277.2012.01811.x
PMCID: PMC3723132  PMID: 22551091
fetal alcohol spectrum disorders (FASD); fetal alcohol syndrome (FAS); brain-behavior correlations; verbal learning/recall; cognitive control
25.  Clinical factors related to brain structure in HIV: the CHARTER study 
Journal of neurovirology  2011;17(3):248-257.
Despite the widening use of combination anti-retroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n=251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.
doi:10.1007/s13365-011-0032-7
PMCID: PMC3702821  PMID: 21544705
HIV; MRI; Neuroimaging; Immunospupression

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