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1.  Developmental Changes in Organization of Structural Brain Networks 
Khundrakpam, Budhachandra S. | Reid, Andrew | Brauer, Jens | Carbonell, Felix | Lewis, John | Ameis, Stephanie | Karama, Sherif | Lee, Junki | Chen, Zhang | Das, Samir | Evans, Alan C. | Ball, William S. | Byars, Anna Weber | Schapiro, Mark | Bommer, Wendy | Carr, April | German, April | Dunn, Scott | Rivkin, Michael J. | Waber, Deborah | Mulkern, Robert | Vajapeyam, Sridhar | Chiverton, Abigail | Davis, Peter | Koo, Julie | Marmor, Jacki | Mrakotsky, Christine | Robertson, Richard | McAnulty, Gloria | Brandt, Michael E. | Fletcher, Jack M. | Kramer, Larry A. | Yang, Grace | McCormack, Cara | Hebert, Kathleen M. | Volero, Hilda | Botteron, Kelly | McKinstry, Robert C. | Warren, William | Nishino, Tomoyuki | Robert Almli, C. | Todd, Richard | Constantino, John | McCracken, James T. | Levitt, Jennifer | Alger, Jeffrey | O'Neil, Joseph | Toga, Arthur | Asarnow, Robert | Fadale, David | Heinichen, Laura | Ireland, Cedric | Wang, Dah-Jyuu | Moss, Edward | Zimmerman, Robert A. | Bintliff, Brooke | Bradford, Ruth | Newman, Janice | Evans, Alan C. | Arnaoutelis, Rozalia | Bruce Pike, G. | Louis Collins, D. | Leonard, Gabriel | Paus, Tomas | Zijdenbos, Alex | Das, Samir | Fonov, Vladimir | Fu, Luke | Harlap, Jonathan | Leppert, Ilana | Milovan, Denise | Vins, Dario | Zeffiro, Thomas | Van Meter, John | Lange, Nicholas | Froimowitz, Michael P. | Botteron, Kelly | Robert Almli, C. | Rainey, Cheryl | Henderson, Stan | Nishino, Tomoyuki | Warren, William | Edwards, Jennifer L. | Dubois, Diane | Smith, Karla | Singer, Tish | Wilber, Aaron A. | Pierpaoli, Carlo | Basser, Peter J. | Chang, Lin-Ching | Koay, Chen Guan | Walker, Lindsay | Freund, Lisa | Rumsey, Judith | Baskir, Lauren | Stanford, Laurence | Sirocco, Karen | Gwinn-Hardy, Katrina | Spinella, Giovanna | McCracken, James T. | Alger, Jeffry R. | Levitt, Jennifer | O'Neill, Joseph
Cerebral Cortex (New York, NY)  2012;23(9):2072-2085.
Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8–8.4 year; late childhood: 8.5–11.3 year; early adolescence: 11.4–14.7 year; late adolescence: 14.8–18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.
doi:10.1093/cercor/bhs187
PMCID: PMC3729193  PMID: 22784607
adolescence; connectivity; connector hub; cortical thickness; maturation
2.  Hierarchical multivariate covariance analysis of metabolic connectivity 
Conventional brain connectivity analysis is typically based on the assessment of interregional correlations. Given that correlation coefficients are derived from both covariance and variance, group differences in covariance may be obscured by differences in the variance terms. To facilitate a comprehensive assessment of connectivity, we propose a unified statistical framework that interrogates the individual terms of the correlation coefficient. We have evaluated the utility of this method for metabolic connectivity analysis using [18F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. As an illustrative example of the utility of this approach, we examined metabolic connectivity in angular gyrus and precuneus seed regions of mild cognitive impairment (MCI) subjects with low and high β-amyloid burdens. This new multivariate method allowed us to identify alterations in the metabolic connectome, which would not have been detected using classic seed-based correlation analysis. Ultimately, this novel approach should be extensible to brain network analysis and broadly applicable to other imaging modalities, such as functional magnetic resonance imaging (MRI).
doi:10.1038/jcbfm.2014.165
PMCID: PMC4269748  PMID: 25294129
Alzheimer's disease; β-amyloid; covariance analysis; FDG PET; florbetapir PET; metabolic connectivity; mild cognitive impairment
3.  Epidemic Spreading Model to Characterize Misfolded Proteins Propagation in Aging and Associated Neurodegenerative Disorders 
PLoS Computational Biology  2014;10(11):e1003956.
Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.
Author Summary
Misfolded proteins (MP) mechanisms are a characteristic pathogenic feature of most prevalent human neurodegenerative diseases, such as Alzheimer's disease (AD). Characterizing the mechanisms underlying intra-brain MP propagation and deposition still constitutes a major challenge. Here, we hypothesize that these complex mechanisms can be accurately described by epidemic spreading-like interactions between infectious-like agents (MP) and the brain's MP clearance response, which are constrained by the brain's connectional architecture. Consequently, we have developed a stochastic epidemic spreading model (ESM) of MP propagation/deposition that allows for reconstructing individual lifetime histories of intra-brain MP propagation, and the subsequent analysis of factors that promote propagation/deposition (e.g., MP production and clearance). Using 733 individual PET Amyloid-ß (Aß) datasets, we show that ESM explains advanced Aß deposition patterns in healthy and diseased (AD) brains. More importantly, it offers new avenues for our understanding of the mechanisms underlying MP mediated disorders. For instance, the results strongly support the growing body of evidence suggesting the leading role of a reduced Aβ clearance on AD progression and the modulatory impact of Aß mechanisms on tau proteins concentrations, which could imply a turning point for associated therapeutic mitigation strategies.
doi:10.1371/journal.pcbi.1003956
PMCID: PMC4238950  PMID: 25412207
4.  Diffusion imaging quality control via entropy of principal direction distribution 
NeuroImage  2013;82:1-12.
Diffusion MR imaging has received increasing attention in the neuroimaging community, as it yields new insights into the microstructural organization of white matter that are not available with conventional MRI techniques. While the technology has enormous potential, diffusion MRI suffers from a unique and complex set of image quality problems, limiting the sensitivity of studies and reducing the accuracy of findings. Furthermore, the acquisition time for diffusion MRI is longer than conventional MRI due to the need for multiple acquisitions to obtain directionally encoded Diffusion Weighted Images (DWI). This leads to increased motion artifacts, reduced signal-to-noise ratio (SNR), and increased proneness to a wide variety of artifacts, including eddy-current and motion artifacts, “venetian blind” artifacts, as well as slice-wise and gradient-wise inconsistencies. Such artifacts mandate stringent Quality Control (QC) schemes in the processing of diffusion MRI data. Most existing QC procedures are conducted in the DWI domain and/or on a voxel level, but our own experiments show that these methods often do not fully detect and eliminate certain types of artifacts, often only visible when investigating groups of DWI's or a derived diffusion model, such as the most-employed diffusion tensor imaging (DTI). Here, we propose a novel regional QC measure in the DTI domain that employs the entropy of the regional distribution of the principal directions (PD). The PD entropy quantifies the scattering and spread of the principal diffusion directions and is invariant to the patient's position in the scanner. High entropy value indicates that the PDs are distributed relatively uniformly, while low entropy value indicates the presence of clusters in the PD distribution. The novel QC measure is intended to complement the existing set of QC procedures by detecting and correcting residual artifacts. Such residual artifacts cause directional bias in the measured PD and here called dominant direction artifacts. Experiments show that our automatic method can reliably detect and potentially correct such artifacts, especially the ones caused by the vibrations of the scanner table during the scan. The results further indicate the usefulness of this method for general quality assessment in DTI studies.
doi:10.1016/j.neuroimage.2013.05.022
PMCID: PMC3798052  PMID: 23684874
Diffusion magnetic resonance imaging; Diffusion tensor imaging; Quality assessment; Entropy
5.  β-Amyloid is associated with aberrant metabolic connectivity in subjects with mild cognitive impairment 
Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein E ɛ4 (APOE ɛ4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ɛ4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ɛ4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.
doi:10.1038/jcbfm.2014.66
PMCID: PMC4083380  PMID: 24736891
APOE ɛ4; β-amyloid; FDG PET; florbetapir PET; metabolic connectivity; mild cognitive impairment
6.  Testosterone-Related Cortical Maturation Across Childhood and Adolescence 
Cerebral Cortex (New York, NY)  2012;23(6):1424-1432.
Neuroendocrine theories of brain development hold testosterone as the predominant factor mediating sex-specific cortical growth and the ensuing lateralization of hemispheric function. However, studies to date have focussed on prenatal testosterone rather than pubertal changes in testosterone. Yet, animal studies have shown a high density of androgen-sensitive receptors in multiple key cortical areas, and puberty is known to coincide with both a significant rise in testosterone and the emergence of behavioral sex differences, suggesting peripubertal influences of testosterone on brain development. Here, we used linear mixed models to examine sex-specific cortical maturation associated with changes in testosterone levels in a longitudinal sample of developmentally healthy children and adolescents. A significant “sex by age by testosterone” interaction on cortical thickness (CTh) involving widespread areas of the developing brain was found. Testosterone levels were associated with CTh changes in regions of the left hemisphere in males and of the right hemisphere in females. In both sexes, the relationship between testosterone and CTh varied across the age span. These findings show the association between testosterone and CTh to be complex, highly dynamic, and to vary, depending on sex and age; they also suggest sex-related hemispheric lateralization effects of testosterone in humans.
doi:10.1093/cercor/bhs125
PMCID: PMC3643718  PMID: 22617851
androgens; brain development; gray matter; puberty; sex
7.  Evidence for a cerebral cortical thickness network anti-correlated with amygdalar volume in healthy youths: implications for the neural substrates of emotion regulation 
NeuroImage  2013;71:42-49.
Recent functional connectivity studies have demonstrated that, in resting humans, activity in a dorsally-situated neocortical network is inversely associated with activity in the amygdalae. Similarly, in human neuroimaging studies, aspects of emotion regulation have been associated with increased activity in dorsolateral, dorsomedial, orbital and ventromedial prefrontal regions, as well as concomitant decreases in amygdalar activity. These findings indicate the presence of two countervailing systems in the human brain that are reciprocally related: a dorsally-situated cognitive control network, and a ventrally-situated limbic network. We investigated the extent to which this functional reciprocity between limbic and dorsal neocortical regions is recapitulated from a purely structural standpoint. Specifically, we hypothesized that amygdalar volume would be related to cerebral cortical thickness in cortical regions implicated in aspects of emotion regulation. In 297 typically developing youths (162 females, 135 males; 572 MRIs), the relationship between cortical thickness and amygdalar volume was characterized. Amygdalar volume was found to be inversely associated with thickness in bilateral dorsolateral and dorsomedial prefrontal, inferior parietal, as well as bilateral orbital and ventromedial prefrontal cortices. Our findings are in line with previous work demonstrating that a predominantly dorsally-centered neocortical network is reciprocally related to core limbic structures such as the amygdalae. Future research may benefit from investigating the extent to which such cortical-limbic morphometric relations are qualified by the presence of mood and anxiety psychopathology.
doi:10.1016/j.neuroimage.2012.12.071
PMCID: PMC3622221  PMID: 23313419
amygdala; cortical thickness; MRI; normal development
8.  Group-wise Cortical Correspondence via Sulcal Curve-Constrained Entropy Minimization 
We present a novel cortical correspondence method employing group-wise registration in a spherical parametrization space for the use in local cortical thickness analysis in human and non-human primate neuroimaging studies. The proposed method is unbiased registration that estimates a continuous smooth deformation field into an unbiased average space via sulcal curve-constrained entropy minimization using spherical harmonic decomposition of the spherical deformation field. We initialize a correspondence by our pair-wise method that establishes a surface correspondence with a prior template. Since this pair-wise correspondence is biased to the choice of a template, we further improve the correspondence by employing unbiased ensemble entropy minimization across all surfaces, which yields a deformation field onto the iteratively updated unbiased average. The specific entropy metric incorporates two terms: the first focused on optimizing the correspondence of automatically extracted sulcal landmarks and the second on that of sulcal depth maps. We also propose an encoding scheme for spherical deformation via spherical harmonics as well as a novel method to choose an optimal spherical polar coordinate system for the most efficient deformation field estimation. The experimental results show evidence that the proposed method improves the correspondence quality in non-human primate and human subjects as compared to the pair-wise method.
PMCID: PMC4003502  PMID: 24683983
Group-wise correspondence; Sulcal curves; Spherical harmonics; Entropy minimization; Cortical thickness
9.  CBRAIN: a web-based, distributed computing platform for collaborative neuroimaging research 
The Canadian Brain Imaging Research Platform (CBRAIN) is a web-based collaborative research platform developed in response to the challenges raised by data-heavy, compute-intensive neuroimaging research. CBRAIN offers transparent access to remote data sources, distributed computing sites, and an array of processing and visualization tools within a controlled, secure environment. Its web interface is accessible through any modern browser and uses graphical interface idioms to reduce the technical expertise required to perform large-scale computational analyses. CBRAIN's flexible meta-scheduling has allowed the incorporation of a wide range of heterogeneous computing sites, currently including nine national research High Performance Computing (HPC) centers in Canada, one in Korea, one in Germany, and several local research servers. CBRAIN leverages remote computing cycles and facilitates resource-interoperability in a transparent manner for the end-user. Compared with typical grid solutions available, our architecture was designed to be easily extendable and deployed on existing remote computing sites with no tool modification, administrative intervention, or special software/hardware configuration. As October 2013, CBRAIN serves over 200 users spread across 53 cities in 17 countries. The platform is built as a generic framework that can accept data and analysis tools from any discipline. However, its current focus is primarily on neuroimaging research and studies of neurological diseases such as Autism, Parkinson's and Alzheimer's diseases, Multiple Sclerosis as well as on normal brain structure and development. This technical report presents the CBRAIN Platform, its current deployment and usage and future direction.
doi:10.3389/fninf.2014.00054
PMCID: PMC4033081  PMID: 24904400
eScience; distributed computing; meta-scheduler; collaborative platform; interoperability; cloud computing; neuroimaging; visualization
10.  Studying variability in human brain aging in a population-based German cohort—rationale and design of 1000BRAINS 
The ongoing 1000 brains study (1000BRAINS) is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR) Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collection of clinical, laboratory, socioeconomic, and environmental data from population-based subjects aged 45–75 years on inclusion. HNR subjects underwent detailed assessments in 2000, 2006, and 2011, and completed annual postal questionnaires on health status. 1000BRAINS accesses these HNR data and applies a separate protocol comprising: neuropsychological tests of attention, memory, executive functions and language; examination of motor skills; ratings of personality, life quality, mood and daily activities; analysis of laboratory and genetic data; and state-of-the-art magnetic resonance imaging (MRI, 3 Tesla) of the brain. The latter includes (i) 3D-T1- and 3D-T2-weighted scans for structural analyses and myelin mapping; (ii) three diffusion imaging sequences optimized for diffusion tensor imaging, high-angular resolution diffusion imaging for detailed fiber tracking and for diffusion kurtosis imaging; (iii) resting-state and task-based functional MRI; and (iv) fluid-attenuated inversion recovery and MR angiography for the detection of vascular lesions and the mapping of white matter lesions. The unique design of 1000BRAINS allows: (i) comprehensive investigation of various influences including genetics, environment and health status on variability in brain structure and function during aging; and (ii) identification of the impact of selected influencing factors on specific cognitive subsystems and their anatomical correlates.
doi:10.3389/fnagi.2014.00149
PMCID: PMC4094912  PMID: 25071558
cohort; connectivity; Heinz Nixdorf Recall Study; resting-state; imaging genetics; variability; aging; elderly
11.  Magnetic resonance imaging of healthy and diseased brain networks 
doi:10.3389/fnhum.2014.00890
PMCID: PMC4217377  PMID: 25404910
connectomics; connectivity; graph theory; small-world; MRI
12.  BrainBrowser: distributed, web-based neurological data visualization 
Recent years have seen massive, distributed datasets become the norm in neuroimaging research, and the methodologies used to analyze them have, in response, become more collaborative and exploratory. Tools and infrastructure are continuously being developed and deployed to facilitate research in this context: grid computation platforms to process the data, distributed data stores to house and share them, high-speed networks to move them around and collaborative, often web-based, platforms to provide access to and sometimes manage the entire system. BrainBrowser is a lightweight, high-performance JavaScript visualization library built to provide easy-to-use, powerful, on-demand visualization of remote datasets in this new research environment. BrainBrowser leverages modern web technologies, such as WebGL, HTML5 and Web Workers, to visualize 3D surface and volumetric neuroimaging data in any modern web browser without requiring any browser plugins. It is thus trivial to integrate BrainBrowser into any web-based platform. BrainBrowser is simple enough to produce a basic web-based visualization in a few lines of code, while at the same time being robust enough to create full-featured visualization applications. BrainBrowser can dynamically load the data required for a given visualization, so no network bandwidth needs to be waisted on data that will not be used. BrainBrowser's integration into the standardized web platform also allows users to consider using 3D data visualization in novel ways, such as for data distribution, data sharing and dynamic online publications. BrainBrowser is already being used in two major online platforms, CBRAIN and LORIS, and has been used to make the 1TB MACACC dataset openly accessible.
doi:10.3389/fninf.2014.00089
PMCID: PMC4292582  PMID: 25628562
visualization; neuroimaging; neurology; WebGL; HTML5
13.  Interactive Effects of Dehydroepiandrosterone and Testosterone on Cortical Thickness during Early Brain Development 
The Journal of Neuroscience  2013;33(26):10840-10848.
Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key endocrine event associated with prepubertal increases in the adrenal production of androgens, most significantly dehydroepiandrosterone (DHEA) and to a certain degree testosterone. Adrenarche also coincides with the emergence of the prosocial and neurobehavioral skills of middle childhood and may therefore represent a human-specific stage of development. Both DHEA and testosterone have been reported in animal and in vitro studies to enhance neuronal survival and programmed cell death depending on the timing, dose, and hormonal context involved, and to potentially compete for the same signaling pathways. Yet no extant brain-hormone studies have examined the interaction between DHEA- and testosterone-related cortical maturation in humans. Here, we used linear mixed models to examine changes in cortical thickness associated with salivary DHEA and testosterone levels in a longitudinal sample of developmentally healthy children and adolescents 4–22 years old. DHEA levels were associated with increases in cortical thickness of the left dorsolateral prefrontal cortex, right temporoparietal junction, right premotor and right entorhinal cortex between the ages of 4–13 years, a period marked by the androgenic changes of adrenarche. There was also an interaction between DHEA and testosterone on cortical thickness of the right cingulate cortex and occipital pole that was most significant in prepubertal subjects. DHEA and testosterone appear to interact and modulate the complex process of cortical maturation during middle childhood, consistent with evidence at the molecular level of fast/nongenomic and slow/genomic or conversion-based mechanisms underlying androgen-related brain development.
doi:10.1523/JNEUROSCI.5747-12.2013
PMCID: PMC3693059  PMID: 23804104
14.  Cortical Correspondence via Sulcal Curve-Constrained Spherical Registration with Application to Macaque Studies 
In this work, we present a novel cortical correspondence method with application to the macaque brain. The correspondence method is based on sulcal curve constraints on a spherical deformable registration using spherical harmonics to parameterize the spherical deformation. Starting from structural MR images, we first apply existing preprocessing steps: brain tissue segmentation using the Automatic Brain Classification tool (ABC), as well as cortical surface reconstruction and spherical parametrization of the cortical surface via Constrained Laplacian-based Automated Segmentation with Proximities (CLASP). Then, initial correspondence between two cortical surfaces is automatically determined by a curve labeling method using sulcal landmarks extracted along sulcal fundic regions. Since the initial correspondence is limited to sulcal regions, we use spherical harmonics to extrapolate and regularize this correspondence to the entire cortical surface. To further improve the correspondence, we compute a spherical registration that optimizes the spherical harmonic parameterized deformation using a metric that incorporates the error over the sulcal landmarks as well as the normalized cross correlation of sulcal depth maps over the whole cortical surface. For evaluation, a normal 18-months-old macaque brain (for both left and right hemispheres) was matched to a prior macaque brain template with 9 manually labeled, major sulcal curves. The results show successful registration using the proposed registration approach. Evaluation results for optimal parameter settings are presented as well.
doi:10.1117/12.2006459
PMCID: PMC3865241  PMID: 24357916
cortical correspondence; surface registration; spherical harmonics; sulcal curve
15.  White Matter Microstructure and Atypical Visual Orienting in 7-Month-Olds at Risk for Autism 
The American journal of psychiatry  2013;170(8):10.1176/appi.ajp.2012.12091150.
Objective
The authors sought to determine whether specific patterns of oculomotor functioning and visual orienting characterize 7-month-old infants who later meet criteria for an autism spectrum disorder (ASD) and to identify the neural correlates of these behaviors.
Method
Data were collected from 97 infants, of whom 16 were high-familial-risk infants later classified as having an ASD, 40 were high-familial-risk infants who did not later meet ASD criteria (high-risk negative), and 41 were low-risk infants. All infants underwent an eye-tracking task at a mean age of 7 months and a clinical assessment at a mean age of 25 months. Diffusion-weighted imaging data were acquired for 84 of the infants at 7 months. Primary outcome measures included average saccadic reaction time in a visually guided saccade procedure and radial diffusivity (an index of white matter organization) in fiber tracts that included corticospinal pathways and the splenium and genu of the corpus callosum.
Results
Visual orienting latencies were longer in 7-month-old infants who expressed ASD symptoms at 25 months compared with both high-risk negative infants and low-risk infants. Visual orienting latencies were uniquely associated with the microstructural organization of the splenium of the corpus callosum in low-risk infants, but this association was not apparent in infants later classified as having an ASD.
Conclusions
Flexibly and efficiently orienting to salient information in the environment is critical for subsequent cognitive and social-cognitive development. Atypical visual orienting may represent an early prodromal feature of an ASD, and abnormal functional specialization of posterior cortical circuits directly informs a novel model of ASD pathogenesis.
doi:10.1176/appi.ajp.2012.12091150
PMCID: PMC3863364  PMID: 23511344
16.  Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma 
Nature genetics  2012;44(11):10.1038/ng.2444.
Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics1-3. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK (OMIM #148600), we report heterozygous loss-of-function mutations in AAGAB, encoding alpha- and gamma-adaptin binding protein p34, at a previously linked locus on 15q22. p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicative of a role in membrane traffic. Ultrastucturally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of p34 in keratinocytes led to increased cell division, which was linked to greatly increased epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and proliferation.
doi:10.1038/ng.2444
PMCID: PMC3836166  PMID: 23064416
17.  Reduced Cortical Thickness in Primary Open-Angle Glaucoma and Its Relationship to the Retinal Nerve Fiber Layer Thickness 
PLoS ONE  2013;8(9):e73208.
Objectives
To examine possible changes in cortical thickness and their relationship to retinal nerve fiber layer (RNFL) thickness in patients with primary open-angle glaucoma (POAG).
Materials and Methods
Thirty-six patients with POAG and 40 matched healthy controls were enrolled in this study. All subjects underwent a comprehensive ophthalmologic examination and a high resolution structural magnetic resonance scan. Cortical thickness analysis was used to assess the changes between patients and controls. Correlations between the thickness of the visual cortex and RNFL thickness were also analyzed. Finally, the relationship between the severity of changes in the visual cortex and RNFL thickness was evaluated by comparing patients with mild and severe groups.
Results
POAG patients showed significant bilateral cortical thinning in the anterior half of the visual cortex around the calcarine sulci (left BA 17 and BA 18, right BA17) and in some smaller regions located in the left middle temporal gyrus (BA37) and fusiform gyrus (BA19). The thickness of the visual cortex correlated positively with RNFL thickness (left, r = 0.44, p = 0.01; right, r = 0.38, p = 0.03). Significant differences between mild and severe groups were observed with regard to both RNFL thickness and the thickness of bilateral visual cortex (p < 0.05).
Conclusion
Our findings indicate that cortical thickness analysis may be sufficiently sensitive to detect cortical alterations in POAG and that the measurement has great potential for clinical application.
doi:10.1371/journal.pone.0073208
PMCID: PMC3760921  PMID: 24019910
18.  Brain Volume Findings in Six Month Old Infants at High Familial Risk for Autism 
The American journal of psychiatry  2012;169(6):601-608.
Objective
Brain enlargement has been observed in individuals with autism as early as two years of age. Studies using head circumference suggest that brain enlargement is a postnatal event that occurs around the latter part of the first year. To date, no brain imaging studies have systematically examined the period prior to age two. In this study we examine MRI brain volume in six month olds at high familial risk for autism.
Method
The Infant Brain Imaging Study (IBIS) is a longitudinal imaging study of infants at high risk for autism. This cross-sectional analysis examines brain volumes at six months of age, in high risk infants (N=98) in comparison to infants without family members with autism (low risk) (N=36). MRI scans are also examined for radiologic abnormalities.
Results
No group differences were observed for intracranial cerebrum, cerebellum, lateral ventricle volumes, or head circumference.
Conclusions
We did not observe significant group differences for head circumference, brain volume, or abnormalities of radiologic findings in a sample of 6 month old infants at high-risk for autism. We are unable to conclude that these changes are not present in infants who later go on to receive a diagnosis of autism, but rather that they were not detected in a large group at high familial risk. Future longitudinal studies of the IBIS sample will examine whether brain volume may differ in those infants who go onto develop autism, estimating that approximately 20% of this sample may be diagnosed with an autism spectrum disorder at age two.
doi:10.1176/appi.ajp.2012.11091425
PMCID: PMC3744332  PMID: 22684595
autism; child psychiatry
19.  Differences in White Matter Fiber Tract Development Present from 6 to 24 Months in Infants with Autism 
The American Journal of Psychiatry  2012;169(6):589-600.
OBJECTIVE
Evidence from prospective high-risk infant studies suggests that early symptoms of autism usually emerge late in the first- or early in the second-year of life after a period of relatively typical development. This is the first neuroimaging study to prospectively examine white matter fiber tract organization during this interval in infants who develop autism spectrum disorder (ASD) by 24 months.
METHOD
Participants included 92 infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months, with a majority contributing additional imaging data at either or both 12 and 24 months. At 24 months, 28 infants met criteria for ASD; 64 infants did not. Microstructural properties of white-matter fiber tracts reported to be associated with ASD or related behaviors were characterized by fractional anisotropy (FA) and radial and axial diffusivity.
RESULTS
FA trajectories differed significantly between infants who did versus did not develop ASD for 12 of 15 fiber tracts. Development for most fiber tracts in infants with ASD was characterized by elevated FA at 6 months followed by slower developmental change overtime relative to infants without ASD. Thus, by 24 months of age, lower FA values were evident for those with ASD.
CONCLUSION
These results suggest that the aberrant development of white matter pathways precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.
doi:10.1176/appi.ajp.2011.11091447
PMCID: PMC3377782  PMID: 22362397
20.  Superficially Located White Matter Structures Commonly Seen in the Human and the Macaque Brain with Diffusion Tensor Imaging 
Brain connectivity  2011;1(1):37-47.
The white matter of the brain consists of fiber tracts that connect different regions of the brain. Among these tracts, the intrahemispheric cortico-cortical connections are called association fibers. The U-fibers are short association fibers that connect adjacent gyri. These fibers were thought to work as part of the cortico-cortical networks to execute associative brain functions. However, their anatomy and functions have not been documented in detail for the human brain. In past studies, U-fibers have been characterized in the human brain with diffusion tensor imaging (DTI). However, the validity of such findings remains unclear. In this study, DTI of the macaque brain was performed, and the anatomy of U-fibers was compared with that of the human brain reported in a previous study. The macaque brain was chosen because it is the most commonly used animal model for exploring cognitive functions and the U-fibers of the macaque brain have been already identified by axonal tracing studies, which makes it an ideal system for confirming the DTI findings. Ten U-fibers found in the macaque brain were also identified in the human brain, with a similar organization and topology. The delineation of these species-conserved white matter structures may provide new options for understanding brain anatomy and function.
doi:10.1089/brain.2011.0005
PMCID: PMC3569096  PMID: 22432953
association fiber; blade; diffusion tensor imaging; macaque, U-fiber; white matter
21.  Topological Organization of Functional Brain Networks in Healthy Children: Differences in Relation to Age, Sex, and Intelligence 
PLoS ONE  2013;8(2):e55347.
Recent studies have demonstrated developmental changes of functional brain networks derived from functional connectivity using graph theoretical analysis, which has been rapidly translated to studies of brain network organization. However, little is known about sex- and IQ-related differences in the topological organization of functional brain networks during development. In this study, resting-state fMRI (rs-fMRI) was used to map the functional brain networks in 51 healthy children. We then investigated the effects of age, sex, and IQ on economic small-world properties and regional nodal properties of the functional brain networks. At a global level of whole networks, we found significant age-related increases in the small-worldness and local efficiency, significant higher values of the global efficiency in boys compared with girls, and no significant IQ-related difference. Age-related increases in the regional nodal properties were found predominately in the frontal brain regions, whereas the parietal, temporal, and occipital brain regions showed age-related decreases. Significant sex-related differences in the regional nodal properties were found in various brain regions, primarily related to the default mode, language, and vision systems. Positive correlations between IQ and the regional nodal properties were found in several brain regions related to the attention system, whereas negative correlations were found in various brain regions primarily involved in the default mode, emotion, and language systems. Together, our findings of the network topology of the functional brain networks in healthy children and its relationship with age, sex, and IQ bring new insights into the understanding of brain maturation and cognitive development during childhood and adolescence.
doi:10.1371/journal.pone.0055347
PMCID: PMC3563524  PMID: 23390528
22.  Decreased Regional Cortical Thickness and Thinning Rate Are Associated with Inattention Symptoms in Healthy Children 
Objective
Children with attention-deficit/hyperactivity disorder (ADHD) have delayed cortical maturation, evidenced by regionally specific slower cortical thinning. However, the relationship between cortical maturation and attention capacities in typically developing children is unknown. This study examines cortical thickness correlates of inattention symptoms in a large sample of healthy children.
Method
Data from 357 healthy subjects (6.0–18.4 years of age) were obtained from the NIH MRI Study of Normal Brain Development. In cross-sectional analysis (first visit, n = 257), Child Behavior Checklist Attention Problems (AP) scores were linearly regressed against cortical thickness, controlling for age, gender, total brain volume, and site. For longitudinal data (up to three visits, n = 357/672 scans), similar analyses were performed using mixed-effects linear regressions. Interactions of AP with age and gender were tested.
Results
A cross-sectional “AP by age” interaction was found in bilateral orbito-frontal cortex, right inferior frontal cortex, bilateral ventromedial prefrontal cortex, bilateral dorsolateral prefrontal cortex, and several additional attention network regions. The interaction was due to negative associations between AP and thickness in younger subjects (6–10 years of age) that gradually disappeared over time secondary to slower cortical thinning. Similar trends were present in longitudinal analyses.
Conclusions
Higher AP scores were associated with thinner cortex at baseline and slower cortical thinning with aging in multiple areas involved in attention processes. Similar patterns have been identified in ADHD, suggesting a dimensional component to the link between attention and cortical maturation. The identified association between cortical maturation and attention in healthy development will help to inform studies of neuroimaging biomarkers of ADHD.
doi:10.1016/j.jaac.2011.09.022
PMCID: PMC3297982  PMID: 22176936
attention-deficit/hyperactivity disorder; Child Behavior Checklist; attention; cortical thickness; magnetic resonance imaging
23.  Network efficiency in autism spectrum disorder and its relation to brain overgrowth 
A substantial body of evidence links differences in brain size to differences in brain organization. We have hypothesized that the developmental aspect of this relation plays a role in autism spectrum disorder (ASD), a neurodevelopmental disorder which involves abnormalities in brain growth. Children with ASD have abnormally large brains by the second year of life, and for several years thereafter their brain size can be multiple standard deviations above the norm. The greater conduction delays and cellular costs presumably associated with the longer long-distance connections in these larger brains is thought to influence developmental processes, giving rise to an altered brain organization with less communication between spatially distant regions. This has been supported by computational models and by findings linking greater intra-cranial volume, an index of maximum brain-size during development, to reduced inter-hemispheric connectivity in individuals with ASD. In this paper, we further assess this hypothesis via a whole-brain analysis of network efficiency. We utilize diffusion tractography to estimate the strength and length of the connections between all pairs of cortical regions. We compute the efficiency of communication between each network node and all others, and within local neighborhoods; we then assess the relation of these measures to intra-cranial volume, and the differences in these measures between adults with autism and typical controls. Intra-cranial volume is shown to be inversely related to efficiency for wide-spread regions of cortex. Moreover, the spatial patterns of reductions in efficiency in autism bear a striking resemblance to the regional relationships between efficiency and intra-cranial volume, particularly for local efficiency. The results thus provide further support for the hypothesized link between brain overgrowth in children with autism and the efficiency of the organization of the brain in adults with autism.
doi:10.3389/fnhum.2013.00845
PMCID: PMC3857605  PMID: 24368901
autism; brain size; network analysis; connectivity; tractography; optimal wiring; scaling
24.  Cerebellar malformations alter regional cerebral development 
AIM
The aim of this study was to compare total and regional cerebral volumes in children with isolated cerebellar malformations (CBMs) with those in typically developing children, and to examine the extent to which cerebellar volumetric reductions are associated with total and regional cerebral volumes.
METHOD
This is a case–control study of children diagnosed with isolated CBMs. Each child was matched on age and sex to two typically developing children. Using advanced three-dimensional volumetric magnetic resonance imaging, the cerebrum was segmented into tissue classes and partitioned into eight regions. Analysis of variance was used to compare cerebral volumes between children with CBMs and comparison children, and linear regressions to examine the impact of cerebellar volume reduction on cerebral volumes.
RESULTS
Magnetic resonance imaging was performed at a mean age of 27 months in 20 children (10 males, 10 females) with CBMs and 40 typically developing children. Children with CBMs showed significantly smaller deep grey matter nuclei (p<0.001), subgenual white matter (p=0.03), midtemporal white matter (p=0.02), and inferior occipital grey matter (p=0.03) volumes than typically developing children. Greater cerebellar volumetric reduction in children with CBMs was associated with decreased total cerebral volume and deep grey matter nuclei (p=0.02), subgenual white/grey matter (p=0.001), midtemporal white (p=0.02) and grey matter (p=0.01), and parieto-occipital grey matter (p=0.004).
INTERPRETATION
CBMs are associated with impaired regional cerebral growth, suggesting deactivation of principal cerebello-cerebral pathways.
doi:10.1111/j.1469-8749.2011.04090.x
PMCID: PMC3220736  PMID: 22066826
25.  Anatomical Substrates of the Alerting, Orienting and Executive Control Components of Attention: Focus on the Posterior Parietal Lobe 
PLoS ONE  2012;7(11):e50590.
Both neuropsychological and functional neuroimaging studies have identified that the posterior parietal lobe (PPL) is critical for the attention function. However, the unique role of distinct parietal cortical subregions and their underlying white matter (WM) remains in question. In this study, we collected both magnetic resonance imaging and diffusion tensor imaging (DTI) data in normal participants, and evaluated their attention performance using attention network test (ANT), which could isolate three different attention components: alerting, orienting and executive control. Cortical thickness, surface area and DTI parameters were extracted from predefined PPL subregions and correlated with behavioural performance. Tract-based spatial statistics (TBSS) was used for the voxel-wise statistical analysis. Results indicated structure-behaviour relationships on multiple levels. First, a link between the cortical thickness and WM integrity of the right inferior parietal regions and orienting performance was observed. Specifically, probabilistic tractography demonstrated that the integrity of WM connectivity between the bilateral inferior parietal lobules mediated the orienting performance. Second, the scores of executive control were significantly associated with the WM diffusion metrics of the right supramarginal gyrus. Finally, TBSS analysis revealed that alerting performance was significant correlated with the fractional anisotropy of local WM connecting the right thalamus and supplementary motor area. We conclude that distinct areas and features within PPL are associated with different components of attention. These findings could yield a more complete understanding of the nature of the PPL contribution to visuospatial attention.
doi:10.1371/journal.pone.0050590
PMCID: PMC3511515  PMID: 23226322

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