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1.  The NIH Toolbox Cognition Battery: Results from a Large Normative Developmental Sample (PING) 
Neuropsychology  2013;28(1):1-10.
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.
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.
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.
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.
PMCID: PMC3925365  PMID: 24219608
Computerized Assessment; Cognitive Development; Socioeconomic Status
2.  White matter microstructural alterations in children with prenatal methamphetamine/polydrug exposure 
Psychiatry research  2012;204(0):140-148.
Little is known about the effects of prenatal methamphetamine exposure on white matter microstructure, and the impact of concomitant alcohol exposure. Diffusion tensor imaging and neurocognitive testing were performed on 21 children with prenatal methamphetamine exposure (age 9.8±1.8 years; 17 also exposed to alcohol), 19 children with prenatal alcohol but not methamphetamine exposure (age 10.8±2.3 years), and 27 typically-developing children (age 10.3±3.3 years). Whole-brain maps of fractional anisotropy (FA) were evaluated using tract-based spatial statistics. Relative to unexposed controls, children with prenatal methamphetamine exposure demonstrated higher FA mainly in left-sided regions, including the left anterior corona radiata (LCR) and corticospinal tract (P<0.05, corrected). Post-hoc analyses of these FA differences showed they likely result more from lower radial diffusivity (RD) than higher axial diffusivity (AD). Relative to the methamphetamine-exposed group, children with prenatal alcohol exposure showed lower FA in frontotemporal regions – particularly the right external capsule (P<0.05, corrected). We failed to find any group-performance interaction (on tests of executive functioning and visuomotor integration) in predicting FA; however, FA in the right external capsule was significantly associated with performance on a test of visuomotor integration across groups (P<0.05). This report demonstrates unique diffusion abnormalities in children with prenatal methamphetamine/polydrug exposure that are distinct from those associated with alcohol exposure alone, and illustrates that these abnormalities in brain microstructure are persistent into childhood and adolescence – long after the polydrug exposure in utero.
PMCID: PMC3634917  PMID: 23149028
methamphetamine; white matter; alcohol; diffusion imaging; teratogen; in utero
Human brain mapping  2011;33(4):10.1002/hbm.21260.
Individuals with heavy prenatal alcohol exposure can experience significant deficits in cognitive and psychosocial functioning and alterations in brain structure that persist into adulthood. In this report, data from 99 participants collected across three sites (Los Angeles and San Diego, California, and Cape Town, South Africa) were analyzed to examine relationships between brain structure, neurocognitive function, facial morphology, and maternal reports of quantities of alcohol consumption during the first trimester. Across study sites, we found highly significant volume reductions in the FASD group for all of the brain regions evaluated. After correcting for scan location, age, and total brain volume, these differences remained significant in some regions of the basal ganglia and diencephalon. In alcohol-exposed subjects, we found that smaller palpebral fissures were significantly associated with reduced volumes in the diencephalon bilaterally, that greater dysmorphology of the philtrum predicted smaller volumes in basal ganglia and diencephalic structures, and that lower IQ scores were associated with both smaller basal ganglia volumes and greater facial dysmorphology. In subjects from South Africa, we found a significant negative correlation between intracranial volume and total number of drinks per week in the first trimester. These results corroborate previous reports that prenatal alcohol exposure is particularly toxic to basal ganglia and diencephalic structures. We extend previous findings by illustrating relationships between specific measures of facial dysmorphology and the volumes of particular subcortical structures, and for the first time show that continuous measures of maternal alcohol consumption during the first trimester relates to overall brain volume reduction.
PMCID: PMC3812802  PMID: 21416562
Prenatal Alcohol Exposure; Teratogenic Effects of alcohol; Facial Abnormalities; Brain Development; Developmental Defects
4.  Along-tract statistics allow for enhanced tractography analysis 
Neuroimage  2011;59(4):3227-3242.
Diffusion imaging tractography is a valuable tool for neuroscience researchers because it allows the generation of individualized virtual dissections of major white matter tracts in the human brain. It facilitates between-subject statistical analyses tailored to the specific anatomy of each participant. There is prominent variation in diffusion imaging metrics (e.g., fractional anisotropy, FA) within tracts, but most tractography studies use a “tract-averaged” approach to analysis by averaging the scalar values from the many streamline vertices in a tract dissection into a single point-spread estimate for each tract. Here we describe a complete workflow needed to conduct an along-tract analysis of white matter streamline tract groups. This consists of 1) A flexible MATLAB toolkit for generating along-tract data based on B-spline resampling and compilation of scalar data at different collections of vertices along the curving tract spines, and 2) Statistical analysis and rich data visualization by leveraging tools available through the R platform for statistical computing. We demonstrate the effectiveness of such an along-tract approach over the tract-averaged approach in an example analysis of 10 major white matter tracts in a single subject. We also show that these techniques easily extend to between-group analyses typically used in neuroscience applications, by conducting an along-tract analysis of differences in FA between 9 individuals with fetal alcohol spectrum disorders (FASDs) and 11 typically-developing controls. This analysis reveals localized differences between FASD and control groups that were not apparent using a tract-averaged method. Finally, to validate our approach and highlight the strength of this extensible software framework, we implement 2 other methods from the literature and leverage the existing workflow tools to conduct a comparison study.
PMCID: PMC3288584  PMID: 22094644
White matter; tractography; diffusion imaging; FASD; B-spline; along-tract
5.  Mapping White Matter Integrity and Neurobehavioral Correlates in Children with Fetal Alcohol Spectrum Disorders 
Brain structural abnormalities and neurocognitive dysfunction have been observed in individuals with fetal alcohol spectrum disorders (FASDs). Little is known about how white matter integrity is related to these functional and morphological deficits. We used a combination of diffusion tensor and T1-weighted magnetic resonance imaging to evaluate white matter integrity in individuals with FASDs and related these findings to neurocognitive deficits. Seventeen children and adolescents with FASDs were compared with 19 typically developing age-and gender-matched controls. Lower fractional anisotropy (FA) was observed in individuals with FASDs relative to controls in the right lateral temporal lobe and bilaterally in the lateral aspects of the splenium of the corpus callosum. White matter density was also lower in some, but not all regions in which FA was lower. FA abnormalities were confirmed to be in areas of white matter in post hoc region of interest analyses, further supporting that less myelin or disorganized fiber tracts are associated with heavy prenatal alcohol exposure. Significant correlations between performance on a test of visuomotor integration and FA in bilateral splenium, but not temporal regions were observed within the FASD group. Correlations between the visuomotor task and FA within the splenium were not significant with in the control group, and were not significant for measures of reading ability. This suggests that this region of white matter is particularly susceptible to damage from prenatal alcohol exposure and that disruption of splenial fibers in this group is associated with poorer visuomotor integration.
PMCID: PMC3567846  PMID: 18256251
FAS; FASDs; DTI; VBM; corpus callosum; visuomotor integration
6.  Effects of Prenatal Alcohol Exposure and ADHD on Adaptive Functioning 
Heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) are associated with adaptive behavior deficits. The present study examined the interaction between these two factors on parent ratings of adaptive behavior.
As part of a multisite study, primary caregivers of 317 children (8–16y, M=12.38) completed the Vineland Adaptive Behavior Scales-II (VABS-II). Four groups of subjects were included: children with prenatal alcohol exposure with (AE+, n = 82) and without ADHD (AE−, n = 34), children with ADHD (ADHD, n = 71), and control children (CON, n = 130). VABS-II domain scores (Communication, Daily Living Skills, Socialization) were examined using separate 2 (Alcohol Exposure [AE]) × 2 (ADHD diagnosis) between-subjects ANCOVAs.
There were significant main effects of AE (p < .001) and ADHD (p < .001) on all VABS-II domains; alcohol-exposed children had lower scores than children without prenatal alcohol exposure and children with ADHD had lower scores than those without ADHD. There was a significant AE × ADHD interaction effect for Communication [F (1, 308) = 7.49, p = .007, partial η2 =.024], but not Daily Living Skills or Socialization domains (ps > .27). Follow up analyses in the Communication domain indicated the effects of ADHD were stronger in comparison subjects (ADHD vs. CON) than exposed subjects (AE+ vs. AE−) and the effects of alcohol exposure were stronger in subjects without ADHD (AE− vs. CON) than in subjects with ADHD (AE+ vs. ADHD).
As found previously, both prenatal alcohol exposure and ADHD increase adaptive behavior deficits in all domains. However, these two factors interact to cause the greatest impairment in children with both prenatal alcohol exposure and ADHD for communication abilities. These results further demonstrate the deleterious effects of prenatal alcohol exposure and broadens our understanding of how ADHD exacerbates behavioral outcomes in this population.
PMCID: PMC3999227  PMID: 24655090
Adaptive behavior; fetal alcohol syndrome (FAS); fetal alcohol spectrum disorders (FASD); attention-deficit/hyperactivity disorder (ADHD)
7.  Abnormal brain activation during working memory in children with prenatal exposure to drugs of abuse: the effects of methamphetamine, alcohol, and polydrug exposure 
NeuroImage  2010;54(4):3067-3075.
Structural and metabolic abnormalities in fronto-striatal structures have been reported in children with prenatal methamphetamine (MA) exposure. The current study was designed to quantify functional alterations to the fronto-striatal circuit in children with prenatal MA exposure using functional magnetic resonance imaging (fMRI). Because many women who use MA during pregnancy also use alcohol, a known teratogen, we examined 50 children (age range 7–15), 19 with prenatal MA exposure, 15 of whom had concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but no MA exposure (ALC group), and 18 unexposed controls (CON group). We hypothesized that MA exposed children would demonstrate abnormal brain activation during a visuospatial working memory (WM) “N-Back” task. As predicted, the MAA group showed less activation than the CON group in many brain areas, including the striatum and frontal lobe in the left hemisphere. The ALC group showed less activation than the MAA group in several regions, including the right striatum. We found an inverse correlation between performance and activity in the striatum in both the CON and MAA groups. However, this relationship was significant in the caudate of the CON group but not the MAA group, and in the putamen of the MAA group but not the CON group. These findings suggest that structural damage in the fronto-striatal circuit after prenatal MA exposure leads to decreased recruitment of this circuit during a WM challenge, and raise the possibility that a rewiring of cortico-striatal networks may occur in children with prenatal MA exposure.
PMCID: PMC4405109  PMID: 21040792
8.  A Longitudinal Study: Changes in Cortical Thickness and Surface Area during Pubertal Maturation 
PLoS ONE  2015;10(3):e0119774.
Sex hormones have been shown to contribute to the organization and function of the brain during puberty and adolescence. Moreover, it has been suggested that distinct hormone changes in girls versus boys may contribute to the emergence of sex differences in internalizing and externalizing behavior during adolescence. In the current longitudinal study, the influence of within-subject changes in puberty (physical and hormonal) on cortical thickness and surface area was examined across a 2-year span, while controlling for age. Greater increases in Tanner Stage predicted less superior frontal thinning and decreases in precuneus surface area in both sexes. Significant Tanner Stage and sex interactions were also seen, with less right superior temporal thinning in girls but not boys, as well as greater decreases in the right bank of the superior temporal sulcus surface area in boys compared to girls. In addition, within-subject changes in testosterone over the 2-year follow-up period were found to relate to decreases in middle superior frontal surface area in boys, but increases in surface area in girls. Lastly, larger increases in estradiol in girls predicted greater middle temporal lobe thinning. These results show that within-subject physical and hormonal markers of puberty relate to region and sex-specific changes in cortical development across adolescence.
PMCID: PMC4368209  PMID: 25793383
9.  fMRI of syntactic processing in typically developing children: structural correlates in the inferior frontal gyrus 
Development of syntactic processing was examined to evaluate maturational processes including left language lateralization functions and increased specialization of brain regions important for syntactic processing. We utilized multimodal methods, including indices of brain activity from fMRI during a syntactic processing task, cortical thickness measurements from structural MRI, and neuropsychological measures. To evaluate hypotheses about increasing lateralization and specialization with development, we examined relationships between cortical thickness and magnitude and spatial activation extent within the left inferior frontal gyrus (IFG) and its right hemisphere homologue. We predicted that increased activation in the left and decreased activation in the right IFG would be associated with increased syntactic proficiency. As predicted, a more mature pattern of increased thickness in the right pars triangularis was associated with decreased activation intensity and extent in the right IFG. These findings suggest a maturational shift towards decreased involvement of the right IFG for syntactic processing. Better syntactic skills were associated with increased activation in the left IFG independent from age, suggesting increased specialization of the left IFG with increased proficiency. Overall, our findings show relationships between structural and functional neurodevelopment that co-occur with improved syntactic processing in critical language regions of the IFG in typically developing children.
PMCID: PMC3129989  PMID: 21743820
Syntax; language; typical development; lateralization; fMRI; multimodal
10.  Puberty Influences Medial Temporal Lobe and Cortical Gray Matter Maturation Differently in Boys Than Girls Matched for Sexual Maturity 
Cerebral Cortex (New York, NY)  2010;21(3):636-646.
Sex differences in age- and puberty-related maturation of human brain structure have been observed in typically developing age-matched boys and girls. Because girls mature 1–2 years earlier than boys, the present study aimed at assessing sex differences in brain structure by studying 80 adolescent boys and girls matched on sexual maturity, rather than age. We evaluated pubertal influences on medial temporal lobe (MTL), thalamic, caudate, and cortical gray matter volumes utilizing structural magnetic resonance imaging and 2 measures of pubertal status: physical sexual maturity and circulating testosterone. As predicted, significant interactions between sex and the effect of puberty were observed in regions with high sex steroid hormone receptor densities; sex differences in the right hippocampus, bilateral amygdala, and cortical gray matter were greater in more sexually mature adolescents. Within sex, we found larger volumes in MTL structures in more sexually mature boys, whereas smaller volumes were observed in more sexually mature girls. Our results demonstrate puberty-related maturation of the hippocampus, amygdala, and cortical gray matter that is not confounded by age, and is different for girls and boys, which may contribute to differences in social and cognitive development during adolescence, and lasting sexual dimorphisms in the adult brain.
PMCID: PMC3041011  PMID: 20713504
11.  Quantitative in vivo evidence for broad regional gradients in the timing of white matter maturation during adolescence 
NeuroImage  2010;54(1):25-31.
A fundamental tenet in the field of developmental neuroscience is that brain maturation generally proceeds from posterior/inferior to anterior/superior. This pattern is thought to underlie the similar timing of cognitive development in related domains, with the dorsal frontal cortices – important for decision making and cognitive control – the last to fully mature. While this caudal to rostral wave of structural development was first qualitatively described for white matter in classical postmortem studies, and has been discussed frequently in the developmental neuroimaging literature and in the popular press, it has never been formally demonstrated continuously and quantitatively across the whole brain with magnetic resonance imaging (MRI). Here we use diffusion imaging to map developmental changes in the white matter in 32 typically-developing individuals age 5-28 years. We then employ a novel meta-statistic that is sensitive to the timing of this developmental trajectory, and use this integrated strategy to both confirm these long-postulated broad regional gradients in the timing of white matter maturation in vivo, and demonstrate a surprisingly smooth transition in the timing of white matter maturational peaks along a caudal-rostral arc in this cross-sectional sample. These results provide further support for the notion of continued plasticity in these regions well into adulthood, and may provide a new approach for the investigation of neurodevelopmental disorders that could alter the timing of this typical developmental sequence.
PMCID: PMC2962725  PMID: 20708693
White matter; myelin; diffusion; DTI; development; gradient
13.  The Neurobiology of Childhood Structural Brain Development: Conception Through Adulthood 
The study of the function and structure of the human brain dates back centuries, when philosophers and physicians theorized about the localization of specific cognitive functions and the structure and organization of underlying brain tissue. In more recent years, the advent of non-invasive techniques such as Magnetic Resonance Imaging (MRI) has allowed scientists unprecedented opportunities to further our understanding not only of structure and function, but of trajectories of brain development in typical and a-typical child and adult populations. In this chapter, we hope to provide a system-level approach to introduce what we have learned about structural brain development from conception through adulthood. We discuss important findings from MRI studies, and the directions that future imaging studies can take in the concerted effort to enhance our understanding of brain development, and thus to enhance our ability to develop interventions for various neuro developmental disorders.
PMCID: PMC4114219  PMID: 24357437
Human brain; Maturation; Cortical thickness; Brain volume; Cortical area; Postnatal and subcortical; Development
14.  The Clinical Utility and Specificity of Parent Report of Executive Function among Children with Prenatal Alcohol Exposure 
Prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) result in behavioral issues related to poor executive function (EF). This overlap may hinder clinical identification of alcohol-exposed children. This study examined the relation between parent and neuropsychological measures of EF and whether parent ratings aid in differential diagnosis. Neuropsychological measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), were administered to four groups of children (8–16 years): alcohol-exposed with ADHD (AE+, n = 80), alcohol-exposed without ADHD (AE−, n = 36), non-exposed with ADHD (ADHD, n = 93), and controls (CON, n = 167). Primary caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF). For parent ratings, multivariate analyses of variance revealed main effects of Exposure and ADHD and an interaction between these factors, with significant differences between all groups on nearly all BRIEF scales. For neuropsychological measures, results indicated main effects of Exposure and ADHD, but no interaction. Discriminant function analysis indicated the BRIEF accurately classifies groups. These findings confirm compounded behavioral, but not neuropsychological, effects in the AE+ group over the other clinical groups. Parent-report was not correlated with neuropsychological performance in the clinical groups and may provide unique information about neurobehavior. Parent-report measures are clinically useful in predicting alcohol exposure regardless of ADHD. Results contribute to a neurobehavioral profile of prenatal alcohol exposure.
PMCID: PMC4228981  PMID: 25033032
Fetal alcohol spectrum disorders (FASD); Fetal alcohol syndrome (FAS); Behavior Rating Inventory of Executive Function (BRIEF); Pediatric neuropsychology; Parent-report; Attention-deficit/hyperactivity disorder (ADHD)
15.  Relationships between Brain Activation and Brain Structure in Normally Developing Children 
Cerebral Cortex (New York, NY)  2009;19(11):2595-2604.
Dynamic changes in brain structure, activation, and cognitive abilities co-occur during development, but little is known about how changes in brain structure relate to changes in cognitive function or brain activity. By using cortical pattern matching techniques to correlate cortical gray matter thickness and functional brain activity over the entire brain surface in 24 typically developing children, we integrated structural and functional magnetic resonance imaging data with cognitive test scores to identify correlates of mature performance during orthographic processing. Fast-naming individuals activated the right fronto-parietal attention network in response to novel fonts more than slow-naming individuals, and increased activation of this network was correlated with more mature brain morphology in the same fronto-parietal region. These relationships remained even after effects of age or general cognitive ability were statistically controlled. These results localized cortical regions where mature morphology corresponds to mature patterns of activation, and may suggest a role for experience in mediating brain structure–activation relationships.
PMCID: PMC2758677  PMID: 19240138
attention; fMRI; imaging; language; morphometry
16.  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.
PMCID: PMC3904347  PMID: 24024963
ALSPAC; Language Impairment; Reading Disability; Dyslexia GWAS; ZNF385D; PING
Neuropsychology  2013;27(6):713-724.
Neuropsychological functioning of individuals with attention-deficit/hyperactivity disorder (ADHD) or heavy prenatal alcohol exposure has been well documented independently. This study examined the interaction between both factors on cognitive performance in children.
As part of a multisite study, 344 children (8-16y, M=12.28, SD=2.52) completed a comprehensive neuropsychological battery. Four subject groups were tested: children with histories of heavy prenatal alcohol exposure (AE) and ADHD (AE+, n=90), alcohol-exposed without ADHD, (AE−, n=38), non-exposed with ADHD (ADHD, n=80), and non-exposed without ADHD (CON, n=136).
Separate 2(AE) × 2(ADHD) MANCOVAs revealed significant main and interactive effects of ADHD and AE on overall WISC-IV, D-KEFS, and CANTAB performance. Individual ANOVAs revealed significant interactions on 2 WISC-IV indices [Verbal Comprehension (VCI), Perceptual Reasoning (PRI)], and four D-KEFS and CANTAB subtests [Design Fluency, Verbal Fluency, Trail Making, Spatial Working Memory]. Follow-up analyses demonstrated no difference between AE+ and AE− groups on any measures. The combined AE+/− group demonstrated more severe impairment than the ADHD group on VCI and PRI, but there were no other differences between clinical groups.
These results support a combined AE+/− group for neuropsychological research and indicate that, in some cases, the neuropsychological effects seen in ADHD are altered by prenatal alcohol exposure. The effects of alcohol exposure on verbal comprehension and perceptual reasoning were greater than those related to having ADHD without alcohol exposure, although both conditions independently resulted in cognitive impairment compared to controls. Clinically, these findings demonstrate task-dependent patterns of impairment across clinical disorders.
PMCID: PMC3898510  PMID: 24040921
fetal alcohol spectrum disorders (FASD); fetal alcohol syndrome (FAS); Attention-deficit/hyperactivity disorder (ADHD); neurobehavioral profile; specificity
18.  Differentiating prenatal exposure to methamphetamine and alcohol versus alcohol and not methamphetamine using tensor based brain morphometry and discriminant analysis 
Here we investigate the effects of prenatal exposure to methamphetamine (MA) on local brain volume using magnetic resonance imaging. Because many who use MA during pregnancy also use alcohol, a known teratogen, we examined whether local brain volumes differed among 61 children (ages 5 to 15), 21 with prenatal MA exposure, 18 with concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but not MA exposure (ALC group), and 27 unexposed controls (CON group). Volume reductions were observed in both exposure groups relative to controls in striatal and thalamic regions bilaterally, and right prefrontal and left occipitoparietal cortices. Striatal volume reductions were more severe in the MAA group than in the ALC group, and within the MAA group, a negative correlation between full-scale IQ (FSIQ) scores and caudate volume was observed. Limbic structures including the anterior and posterior cingulate, the inferior frontal gyrus (IFG) and ventral and lateral temporal lobes bilaterally were increased in volume in both exposure groups. Further, cingulate and right IFG volume increases were more pronounced in the MAA than ALC group. Discriminant function analyses using local volume measurements and FSIQ were used to predict group membership, yielding factor scores that correctly classified 72% of participants in jackknife analyses. These findings suggest that striatal and limbic structures, known to be sites of neurotoxicity in adult MA abusers, may be more vulnerable to prenatal MA exposure than alcohol exposure, and that more severe striatal damage is associated with more severe cognitive deficit.
PMCID: PMC2847574  PMID: 20237258
Teratogen; cognitive; development; imaging; neurobehavioral; Methamphetamine
19.  Effects of prenatal methamphetamine exposure on verbal memory revealed with fMRI 
Efforts to understand specific effects of prenatal methamphetamine exposure on cognitive processing are hampered by high rates of concomitant alcohol use during pregnancy. We examined whether neurocognitive systems differed among children with differing prenatal teratogenic exposures when they engaged in a verbal memory task.
Patients and Methods
Participants (7-15 years old) engaged in a verbal paired associate learning task while undergoing functional magnetic resonance imaging. The MA group included 14 children with prenatal methamphetamine exposure, 12 of whom had concomitant alcohol exposure. They were compared to 9 children with prenatal alcohol but not methamphetamine exposure (ALC) and 20 unexposed controls (CON). Groups did not differ in age, gender, or socioeconomic status. Participants’ IQ and verbal learning performance were measured using standardized instruments.
The MA group activated more diffuse brain regions, including bilateral medial temporal structures known to be important for memory, than both the ALC and the CON groups. These group differences remained after IQ was covaried. More activation in medial temporal structures by the MA group compared to the ALC group cannot be explained by performance differences because both groups performed at similar levels on the verbal memory task.
More diffuse activation in the MA group during verbal memory may reflect recruitment of compensatory systems to support a weak verbal memory network. Differences in activation patterns between the MA and ALC groups suggest that prenatal MA exposure influences the development of the verbal memory system above and beyond effects of prenatal alcohol exposure.
PMCID: PMC2745202  PMID: 19525715
Teratogen; cognitive; development; imaging; neurobehavioral
20.  Abnormal Cortical Thickness and Brain–Behavior Correlation Patterns in Individuals with Heavy Prenatal Alcohol Exposure 
Quantitative magnetic resonance imaging (MRI) studies in children with fetal alcohol spectrum disorders (FASDs) have shown regional patterns of dysmorphology, most prominent in parietal and posterior temporal cortices. Various methods of image analysis have been employed in these studies, but abnormalities in cortical thickness have not yet been mapped over the entire cortical surface in individuals with FASD. Further, relationships between cognitive dysfunction and cortical thickness measures have not yet been explored. We applied cortical pattern matching algorithms and techniques for measuring cortical thickness in millimeters to the structural brain MRI images of 21 subjects with heavy prenatal alcohol exposure (8–22 years, mean age 12.6 years), and 21 normally developing control subjects (8–25 years, mean age 13.5 years). Dissociable cognitive measures, of verbal recall and visuospatial functioning, were correlated with cortical thickness, and group by test score interactions were evaluated for predicting cortical thickness. Significant cortical thickness excesses of up to 1.2 mm were observed in the FASD subjects in large areas of bilateral temporal, bilateral inferior parietal, and right frontal regions. Significant group by test score interactions were found in right dorsal frontal regions for the verbal recall measure and in left occipital regions for the visuospatial measure. These results are consistent with earlier analyses from our own and other research groups, but for the first time, we show that cortical thickness is also increased in right lateral frontal regions in children with prenatal alcohol exposure. Further, the significant interactions show for the first time that brain-behavior relationships are altered as a function of heavy prenatal alcohol exposure.
PMCID: PMC2770438  PMID: 17443018
FAS; frontal lobe; prenatal alcohol exposure; verbal learning; visuospatial
21.  Neurodevelopmental Changes in Verbal Working Memory Load-Dependency: An fMRI Investigation 
NeuroImage  2008;42(4):1678-1685.
Development of working memory (WM) aptitude parallels structural changes in the frontal-parietal association cortices important for performance within this cognitive domain. The cerebellum has been proposed to function in support of the postulated phonological loop component of verbal WM, and along with frontal and parietal cortices, has been shown to exhibit linear WM load-dependent activation in adults. It is not known if these kinds of WM load-dependent relationships exist for cerebro-cerebellar networks in developmental populations, and whether there are age-related changes in the nature of load-dependency between childhood, adolescence, and adulthood. The present study used fMRI and a verbal Sternberg WM task with three load levels to investigate developmental changes in WM load-dependent cerebro-cerebellar activation in a sample of 30 children, adolescents, and young adults between the ages of 7 and 28. The neural substrates of linear load-dependency were found to change with age. Among adolescents and adults, frontal, parietal and cerebellar regions showed linear load-dependency, or increasing activation under conditions of increasing WM load. In contrast, children recruited only left ventral prefrontal cortex in response to increasing WM load. These results demonstrate that, while children, adolescents, and young adults activate similar cerebro-cerebellar verbal working memory networks, the extent to which they rely on parietal and cerebellar regions in response to increasing task difficulty changes significantly between childhood and adolescence.
PMCID: PMC2570587  PMID: 18586110
22.  White matter microstructure abnormalities and executive function in adolescents with prenatal cocaine exposure 
Psychiatry research  2013;213(2):10.1016/j.pscychresns.2013.04.002.
Children with prenatal exposure to cocaine are at higher risk for negative behavioral function and attention difficulties, and have demonstrated brain diffusion abnormalities in frontal white matter regions. However, brain regions beyond frontal and callosal areas have not been investigated using diffusion tensor imaging (DTI). DTI data were collected on 42 youth aged 14–16 years; subjects were divided into three groups based on detailed exposure histories: those with prenatal exposure to cocaine but not alcohol (PCE, n=12), prenatal exposure to cocaine and alcohol (CAE, n=17), and controls (n=13). Tractography was performed and along-tract diffusion parameters were examined for group differences and correlations with executive function measures. In the right arcuate fasciculus and cingulum, the CAE group had higher fractional anisotropy (FA) and/or lower mean diffusivity (MD) than the other two groups. The PCE group demonstrated lower FA in the right arcuate and higher MD in the splenium of the corpus callosum than controls. Diffusion parameters in tracts with group differences correlated with measures of executive function. In conclusion, these diffusion differences in adolescents with prenatal cocaine exposure suggest localized, long-term structural brain alterations that may underlie attention and response inhibition difficulties.
PMCID: PMC3812806  PMID: 23769420
diffusion tensor imaging; magnetic resonance imaging; white matter; tractography
23.  Sex Differences in Cortical Thickness Mapped in 176 Healthy Individuals between 7 and 87 Years of Age 
Findings from previous magnetic resonance imaging studies of sex differences in gray matter have been inconsistent, with some showing proportionally increased gray matter in women and some showing no differences between the sexes. Regional sex differences in gray matter thickness have not yet been mapped over the entire cortical surface in a large sample of subjects spanning the age range from early childhood to old age. We applied algorithms for cortical pattern matching and techniques for measuring cortical thickness to the structural magnetic resonance images of 176 healthy individuals between the ages of 7 and 87 years. We also mapped localized differences in brain size. Maps of sex differences in cortical thickness revealed thicker cortices in women in right inferior parietal and posterior temporal regions even without correcting for total brain volume. In these regions, the cortical mantle is up to 0.45 mm thicker, on average, in women than in men. Analysis of a subset of 18 female and 18 male subjects matched for age and brain volume confirmed the significance of thicker gray matter in temporal and parietal cortices in females, independent of brain size differences. Further analyses were conducted in the adult subjects where gender differences were evaluated using height as a covariate, and similar sex differences were observed even when body size differences between the sexes were controlled. Together, these results suggest that greater cortical thickness in posterior temporal inferior parietal regions in females relative to males are independent of differences in brain or body size. Age-by-sex interactions were not significant in the temporoparietal region, suggesting that sex differences in these regions are present from at least late childhood and then are maintained throughout life. Male brains were larger than female brains in all locations, though male enlargement was most prominent in the frontal and occipital poles, bilaterally. Given the large sample and the large range of ages studied, these results help to address controversies in the study of central nervous system sexual dimorphisms.
PMCID: PMC2329809  PMID: 16945978
brain size; gender; gray matter; MRI; parietal lobes; temporal lobes
24.  A Commonly Carried Genetic Variant in the Delta Opioid Receptor Gene, OPRD1, is Associated with Smaller Regional Brain Volumes: Replication in Elderly and Young Populations 
Human brain mapping  2013;35(4):1226-1236.
Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.
PMCID: PMC4046708  PMID: 23427138
neuroimaging; genetics; neurodegeneration; drug addiction; opiates
25.  Further Development of a Neurobehavioral Profile of Fetal Alcohol Spectrum Disorders 
Heavy prenatal alcohol exposure (AE) results in a broad array of neurobehavioral deficits. Recent research has focused on identification of a neurobehavioral profile or profiles that will improve identification of children affected by AE. The current study aimed to build on our preliminary neurobehavioral profile in order to improve classification accuracy and test the specificity of the resulting profile in an alternate clinical group.
A standardized neuropsychological test battery was administered to three groups of children: subjects with AE (n = 209), typically developing controls (CON, n = 185), and subjects with attention-deficit/hyperactivity disorder (ADHD, n = 74). We assessed a large sample from six sites in the U.S. and South Africa, using standardized methodology. Data were analyzed using three latent profile analyses (LPA) including: (1) subjects with FAS and controls, (2) subjects with AE without FAS and controls, (3) subjects with AE (with or without FAS) and subjects with ADHD.
Classification accuracy was moderate but significant across the three analyses. In analysis 1, overall classification accuracy was 76.1% (77.2% FAS, 75.7% CON). In the second analysis, overall classification accuracy was 71.5% (70.1% AE/Non-FAS, 72.4% CON). In the third analysis, overall classification accuracy was 73.9% (59.8% AE, 75.7% ADHD). Subjects that were misclassified were examined for systematic differences from those that were correctly classified.
The results of this study indicate that the neuropsychological effects of AE are clinically meaningful and can be used to accurately distinguish alcohol-affected children from both typically developing children and children with ADHD. Further, in combination with other recent studies, these data suggest that approximately 70% of children with heavy prenatal alcohol exposure are neurobehaviorally affected while the remaining 30% are spared these often-devastating consequences, at least those in the domains under study. Refining the neurobehavioral profile will allow improved identification and treatment development for children affected by prenatal alcohol exposure.
PMCID: PMC3524344  PMID: 22974253
Fetal Alcohol Syndrome (FAS); Prenatal Alcohol Exposure; Neurobehavioral Profile; Attention-Deficit/Hyperactivity Disorder (ADHD); Latent Profile Analysis (LPA)

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