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1.  EnigmaVis: online interactive visualization of genome-wide association studies of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium 
Summary
In an attempt to increase power to detect genetic associations with brain phenotypes derived from human neuroimaging data, we recently conducted a large-scale genome-wide association meta-analysis of hippocampal, brain, and intracranial volume through the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. Here we present a freely-available online interactive tool, EnigmaVis, which makes it easy to visualize the association results generated by the consortium alongside allele frequency, genes, and functional annotations. EnigmaVis runs natively within the web browser, and generates plots that show the level of association between brain phenotypes at user-specified genomic positions. Uniquely, EnigmaVis is dynamic; users can interact with elements on the plot in real time. This software will be useful when exploring the effect on brain structure of particular genetic variants influencing neuropsychiatric illness and cognitive function. Future projects of the consortium and updates to EnigmaVis will also be displayed on the site. EnigmaVis is freely available online at http://enigma.loni.ucla.edu/enigma-vis/.
doi:10.1017/thg.2012.17
PMCID: PMC3635713  PMID: 22856375
2.  Bridging the Hemispheres in Meditation: thicker callosal regions and enhanced fractional anisotropy (FA) in long-term practitioners 
Neuroimage  2012;61(1):181-187.
Recent findings suggest a close link between long-term meditation practices and the structure of the corpus callosum. Prior analyses, however, have focused on estimating mean fractional anisotropy (FA) within two large pre-defined callosal tracts only. Additional effects might exist in other, non-explored callosal regions and/or with respect to callosal attributes not captured by estimates of FA. To further explore callosal features in the framework of meditation, we analyzed 30 meditators and 30 controls, carefully matched for sex, age, and handedness. We applied a multimodal imaging approach using diffusion tensor imaging (DTI) in combination with structural magnetic resonance imaging (MRI). Callosal measures of tract-specific FA were complemented with other global (segment-specific) estimates as well as extremely local (point-wise) measures of callosal micro- and macro-structure. Callosal measures were larger in long-term meditators compared to controls, particularly in anterior callosal sections. However, differences achieved significance only when increasing the regional sensitivity of the measurement (i.e., using point-wise measures versus segment-specific measures) and were more prominent for microscopic than macroscopic characteristics (i.e., callosal FA versus callosal thickness). Thicker callosal regions and enhanced FA in meditators might indicate greater connectivity, possibly reflecting increased hemispheric integration during cerebral processes involving (pre)frontal regions. Such a brain organization might be linked to achieving characteristic mental states and skills as associated with meditation, though this hypothesis requires behavioral confirmation. Moreover, longitudinal studies are required to address whether the observed callosal effects are induced by meditation or constitute an innate prerequisite for the start or successful continuation of meditation.
doi:10.1016/j.neuroimage.2012.02.026
PMCID: PMC3345952  PMID: 22374478
brain; corpus callosum; DTI; mindfulness; MRI; plasticity
3.  The Center for Computational Biology: resources, achievements, and challenges 
The Center for Computational Biology (CCB) is a multidisciplinary program where biomedical scientists, engineers, and clinicians work jointly to combine modern mathematical and computational techniques, to perform phenotypic and genotypic studies of biological structure, function, and physiology in health and disease. CCB has developed a computational framework built around the Manifold Atlas, an integrated biomedical computing environment that enables statistical inference on biological manifolds. These manifolds model biological structures, features, shapes, and flows, and support sophisticated morphometric and statistical analyses. The Manifold Atlas includes tools, workflows, and services for multimodal population-based modeling and analysis of biological manifolds. The broad spectrum of biomedical topics explored by CCB investigators include the study of normal and pathological brain development, maturation and aging, discovery of associations between neuroimaging and genetic biomarkers, and the modeling, analysis, and visualization of biological shape, form, and size. CCB supports a wide range of short-term and long-term collaborations with outside investigators, which drive the center's computational developments and focus the validation and dissemination of CCB resources to new areas and scientific domains.
doi:10.1136/amiajnl-2011-000525
PMCID: PMC3277626  PMID: 22081221
National centers for biomedical computing; NCBC; center for computational biology; computational neuroscience; atlas; manifold; computational infrastructure; collaborative and sustainable biomedical research; neuroscience; neuroimaging; data sharing; data mining; brain; segmentation
4.  The Clinical Value of Large Neuroimaging Data Sets in Alzheimer’s Disease 
doi:10.1016/j.nic.2011.11.008
PMCID: PMC3555557  PMID: 22284737
5.  Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 
Brain connectivity  2011;1(6):447-459.
Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 females, 119 males, age: 23.4 +/−2.17 SD years) were scanned with 105-gradient high angular diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual’s co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole brain analyses, as well as greater eccentricity (maximum path length) in 60 of 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study to link graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of circuits implicated in risk for autism.
doi:10.1089/brain.2011.0064
PMCID: PMC3420970  PMID: 22500773
structural connectivity; HARDI; autism; CNTNAP2; graph theory; twins
6.  Delayed White Matter Growth Trajectory in Young Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia 
Archives of general psychiatry  2012;69(9):875-884.
Context
Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings.
Objective
To study WM growth differences in non-psychotic siblings of patients with COS.
Design
Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis.
Setting
National Institutes of Health Clinical Center, Bethesda, Maryland.
Participants
Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1[5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9[5.3] years; 29 male, 28 female).
Intervention
Magnetic resonance imaging.
Main Outcome Measure
White matter growth rates.
Results
We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P =.004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction.
Conclusions
In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.
doi:10.1001/archgenpsychiatry.2011.2084
PMCID: PMC4332876  PMID: 22945617
7.  The link between callosal thickness and intelligence in healthy children and adolescents 
NeuroImage  2010;54(3):1823-1830.
The link between brain structure and intelligence is a well-investigated topic, but existing analyses have mainly focused on adult samples. Studies in healthy children and adolescents are rare, and normative data specifically addressing the association between corpus callosum morphology and intellectual abilities is quite limited. To advance this field of research, we mapped the correlations between standardized intelligence measures and callosal thickness based on high-resolution magnetic resonance imaging (MRI) data. Our large and well-matched sample included 200 normally developing subjects (100 males, 100 females) ranging from 6 to 17 years of age. Although the strongest correlations were negative and confined to the splenium, the strength and the direction of intelligence-callosal thickness associations varied considerably with respect to age and sex. While significant correlations in females were mainly positive, significant correlations in males were exclusively negative. However, only the negative correlations in the overall sample (i.e., males and females combined) remained significant when controlling for multiple comparisons. The observed negative correlations between callosal thickness and intelligence in children and adolescents contrast with the positive correlations typically reported in adult samples. However, negative correlations are in line with reports from other pediatric studies relating cognitive measures to other brain attributes such as cortical thickness, gray matter volume, and gray matter density. Altogether, these findings suggest that relationships between callosal morphology and cognition are highly dynamic during brain maturation. Sex effects on links between callosal thickness and intelligence during childhood and adolescence are present but appear rather weak in general.
doi:10.1016/j.neuroimage.2010.09.083
PMCID: PMC3110814  PMID: 20932920
brain; corpus callosum; development; gender; IQ; MRI
8.  The Unique Brain Anatomy of Meditation Practitioners: Alterations in Cortical Gyrification 
Several cortical regions are reported to vary in meditation practitioners. However, prior analyses have focused primarily on examining gray matter or cortical thickness. Thus, additional effects with respect to other cortical features might have remained undetected. Gyrification (the pattern and degree of cortical folding) is an important cerebral characteristic related to the geometry of the brain’s surface. Thus, exploring cortical gyrification in long-term meditators may provide additional clues with respect to the underlying anatomical correlates of meditation. This study examined cortical gyrification in a large sample (n = 100) of meditators and controls, carefully matched for sex and age. Cortical gyrification was established by calculating mean curvature across thousands of vertices on individual cortical surface models. Pronounced group differences indicating larger gyrification in meditators were evident within the left precentral gyrus, right fusiform gyrus, right cuneus, as well as left and right anterior dorsal insula (the latter representing the global significance maximum). Positive correlations between gyrification and the number of meditation years were similarly pronounced in the right anterior dorsal insula. Although the exact functional implications of larger cortical gyrification remain to be established, these findings suggest the insula to be a key structure involved in aspects of meditation. For example, variations in insular complexity could affect the regulation of well-known distractions in the process of meditation, such as daydreaming, mind-wandering, and projections into past or future. Moreover, given that meditators are masters in introspection, awareness, and emotional control, increased insular gyrification may reflect an integration of autonomic, affective, and cognitive processes. Due to the cross-sectional nature of this study, further research is necessary to determine the relative contribution of nature and nurture to links between cortical gyrification and meditation.
doi:10.3389/fnhum.2012.00034
PMCID: PMC3289949  PMID: 22393318
brain; cortical complexity; curvature; folding; insula; meditation; mindfulness; MRI
9.  Practical management of heterogeneous neuroimaging metadata by global neuroimaging data repositories 
Rapidly evolving neuroimaging techniques are producing unprecedented quantities of digital data at the same time that many research studies are evolving into global, multi-disciplinary collaborations between geographically distributed scientists. While networked computers have made it almost trivial to transmit data across long distances, collecting and analyzing this data requires extensive metadata if the data is to be maximally shared. Though it is typically straightforward to encode text and numerical values into files and send content between different locations, it is often difficult to attach context and implicit assumptions to the content. As the number of and geographic separation between data contributors grows to national and global scales, the heterogeneity of the collected metadata increases and conformance to a single standardization becomes implausible. Neuroimaging data repositories must then not only accumulate data but must also consolidate disparate metadata into an integrated view. In this article, using specific examples from our experiences, we demonstrate how standardization alone cannot achieve full integration of neuroimaging data from multiple heterogeneous sources and why a fundamental change in the architecture of neuroimaging data repositories is needed instead.
doi:10.3389/fninf.2012.00008
PMCID: PMC3311229  PMID: 22470336
image metadata; file format; data archive
10.  Genetics of Path Lengths in Brain Connectivity Networks: HARDI-Based Maps in 457 Adults 
Brain connectivity analyses are increasingly popular for investigating organization. Many connectivity measures including path lengths are generally defined as the number of nodes traversed to connect a node in a graph to the others. Despite its name, path length is purely topological, and does not take into account the physical length of the connections. The distance of the trajectory may also be highly relevant, but is typically overlooked in connectivity analyses. Here we combined genotyping, anatomical MRI and HARDI to understand how our genes influence the cortical connections, using whole-brain tractography. We defined a new measure, based on Dijkstra’s algorithm, to compute path lengths for tracts connecting pairs of cortical regions. We compiled these measures into matrices where elements represent the physical distance traveled along tracts. We then analyzed a large cohort of healthy twins and show that our path length measure is reliable, heritable, and influenced even in young adults by the Alzheimer’s risk gene, CLU.
doi:10.1007/978-3-642-33530-3_3
PMCID: PMC4288784  PMID: 25584366
Structural connectivity; neuroimaging genetics; Dijkstra’s algorithm; HARDI tractography; path length
11.  Why Size Matters: Differences in Brain Volume Account for Apparent Sex Differences in Callosal Anatomy 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.09.040.
Numerous studies have demonstrated a sexual dimorphism of the human corpus callosum. However, the question remains if sex differences in brain size, which typically is larger in men than in women, or biological sex per se account for the apparent sex differences in callosal morphology. Comparing callosal dimensions between men and women matched for overall brain size may clarify the true contribution of biological sex, as any observed group difference should indicate pure sex effects. We thus examined callosal morphology in 24 male and 24 female brains carefully matched for overall size. In addition, we selected 24 extremely large male brains and 24 extremely small female brains to explore if observed sex effects might vary depending on the degree to which male and female groups differed in brain size. Using the individual T1-weighted brain images (n=96), we delineated the corpus callosum at midline and applied a well-validated surface-based mesh-modeling approach to compare callosal thickness at 100 equidistant points between groups determined by brain size and sex. The corpus callosum was always thicker in men than in women. However, this callosal sex difference was strongly determined by the cerebral sex difference overall. That is, the larger the discrepancy in brain size between men and women, the more pronounced the sex difference in callosal thickness, with hardly any callosal differences remaining between brain-size matched men and women. Altogether, these findings suggest that individual differences in brain size account for apparent sex differences in the anatomy of the corpus callosum.
doi:10.1016/j.neuroimage.2013.09.040
PMCID: PMC3867125  PMID: 24064068
Brain; Corpus Callosum; Gender; MRI; Sex
12.  Irritable Bowel Syndrome in female patients is associated with alterations in structural brain networks 
Pain  2013;155(1):137-149.
Alterations in gray matter (GM) density/ volume and cortical thickness (CT) have been demonstrated in small and heterogeneous samples of subjects with different chronic pain syndromes, including irritable bowel syndrome (IBS). Aggregating across 7 structural neuroimaging studies conducted at UCLA between August 2006 and April 2011, we examined group differences in regional GM volume in 201 predominantly premenopausal female subjects (82 IBS, mean age: 32 ± 10 SD, 119 Healthy Controls [HCs], 30± 10 SD). Applying graph theoretical methods and controlling for total brain volume, global and regional properties of large-scale structural brain networks were compared between IBS and HC groups. Relative to HCs, the IBS group had lower volumes in bilateral superior frontal gyrus, bilateral insula, bilateral amygdala, bilateral hippocampus, bilateral middle orbital frontal gyrus, left cingulate, left gyrus rectus, brainstem, and left putamen. Higher volume was found for the left postcentral gyrus. Group differences were no longer significant for most regions when controlling for Early Trauma Inventory global score with the exception of the right amygdala and the left post central gyrus. No group differences were found for measures of global and local network organization. Compared to HCs, the right cingulate gyrus and right thalamus were identified as significantly more critical for information flow. Regions involved in endogenous pain modulation and central sensory amplification were identified as network hubs in IBS. Overall, evidence for central alterations in IBS was found in the form of regional GM volume differences and altered global and regional properties of brain volumetric networks.
doi:10.1016/j.pain.2013.09.020
PMCID: PMC4100785  PMID: 24076048
chronic pain; irritable bowel syndrome; gray matter volume; brain network analysis; graph theory
13.  Gene Interactions and Structural Brain Change in Early-Onset Alzheimer's Disease Subjects Using the Pipeline Environment 
Psychiatry Investigation  2015;12(1):125-135.
Objective
This article investigates subjects aged 55 to 65 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to broaden our understanding of early-onset (EO) cognitive impairment using neuroimaging and genetics biomarkers.
Methods
Nine of the subjects had EO-AD (Alzheimer's disease) and 27 had EO-MCI (mild cognitive impairment). The 15 most important neuroimaging markers were extracted with the Global Shape Analysis (GSA) Pipeline workflow. The 20 most significant single nucleotide polymorphisms (SNPs) were chosen and were associated with specific neuroimaging biomarkers.
Results
We identified associations between the neuroimaging phenotypes and genotypes for a total of 36 subjects. Our results for all the subjects taken together showed the most significant associations between rs7718456 and L_hippocampus (volume), and between rs7718456 and R_hippocampus (volume). For the 27 MCI subjects, we found the most significant associations between rs6446443 and R_superior_frontal_gyrus (volume), and between rs17029131 and L_Precuneus (volume). For the nine AD subjects, we found the most significant associations between rs16964473 and L_rectus gyrus (surface area), and between rs12972537 and L_rectus_gyrus (surface area).
Conclusion
We observed significant correlations between the SNPs and the neuroimaging phenotypes in the 36 EO subjects in terms of neuroimaging genetics. However, larger sample sizes are needed to ensure that the effects will be detectable for a reasonable false-positive error rate using the GSA and Plink Pipeline workflows.
doi:10.4306/pi.2015.12.1.125
PMCID: PMC4310910
Alzheimer's disease; Early-onset; ADNI; Mild cognitive impairment; Memory; Neuroimaging; Genetics
14.  The Development of the Corpus Callosum in the Healthy Human Brain 
The corpus callosum changes structurally throughout life, but most dramatically during childhood and adolescence. Even so, existing studies of callosal development tend to use parcellation schemes that may not capture the complex spatial profile of anatomical changes. Thus, more detailed mapping of callosal growth processes is desirable to create a normative reference. This will help to relate and interpret other structural, functional, and behavioral measurements, both from healthy subjects and pediatric patients. We applied computational surface-based mesh-modeling methods to analyze callosal morphology at extremely high spatial resolution. We mapped callosal development and explored sex differences in a large and well-matched sample of healthy children and adolescents (n=190) aged 5 to 18 years. Except for the rostrum in females, callosal thickness increased across the whole surface, with sex- and region-specific rates of growth, and also shrinkage at times. The temporally distinct changes in callosal thickness are likely to be a consequence of varying degrees of axonal myelination, redirection, and pruning. Alternating phases of callosal growth and shrinkage may reflect a permanent adjustment and fine-tuning of fibers connecting homologous cortical areas during childhood and adolescence. Our findings emphasize the importance of taking into account sex differences in future studies, as existing developmental effects might remain disguised (or biased towards the effect of the dominant sex in unbalanced statistical designs) when pooling male and female samples.
doi:10.1523/JNEUROSCI.5122-09.2010
PMCID: PMC3197828  PMID: 20720105
Age; Female; Isthmus; Male; MRI; Sex; Splenium
15.  Asymmetries of cortical thickness: effects of handedness, sex, and schizophrenia 
Neuroreport  2007;18(14):1427-1431.
Sex, handedness, and disease processes in schizophrenia may affect the magnitude and/or direction of structural brain asymmetries. Using MRI data from 67 healthy (30 men, 10 nondextral) and 84 schizophrenia patients (60 men, 16 nondextral), cortical thickness asymmetries were compared at high spatial resolution. Within-group asymmetries were observed in sensorimotor, perisylvian, and parahippocampal cortices (leftward) and in anterior mesial frontal cortices (rightward). Asymmetry patterns were similar across diagnosis and sex, although some regional asymmetry increases were observed in men. Hand preference (dextrality) significantly influenced regional asymmetries in parietal association and dorsomedial frontal cortices (false discovery rate-corrected), where medial-frontal regions showed diagnosis by dextrality effects (uncorrected). Thus, dextrality relates to cortical thickness asymmetries, although schizophrenia may differentially affect asymmetry patterns across handedness.
doi:10.1097/WNR.0b013e3282e9a5a2
PMCID: PMC3197832  PMID: 17712268
cortical thickness; laterality; magnetic resonance imaging; schizophrenia
16.  Callosal morphology in Williams syndrome: a new evaluation of shape and thickness 
Neuroreport  2007;18(3):203-207.
We applied novel mesh-based geometrical modeling methods to calculate and compare the thickness of the corpus callosum at high spatial resolution and to create pro¢les of average callosal shape in a well-matched sample (n=24) of individuals with Williams syndrome and controls. In close agreement with previous observations, superimposed surface maps indicate that the corpus callosum in Williams syndrome individuals is shorter and less curved. Moreover, we observed significantly thinner callosal regions in Williams syndrome individuals across the posterior surface, where group effects were less pronounced and spatially restricted in brain-size-adjusted data compared with native data. Circumscribed structural alterations in callosal morphology might be candidate anatomic substrates for the unique cognitive and behavioral profile associated with Williams syndrome.
doi:10.1097/WNR.0b013e3280115942
PMCID: PMC3197850  PMID: 17314657
bending; corpus callosum; isthmus; magnetic resonance imaging; morphology; shape; splenium
17.  Multimodal, Multidimensional Models of Mouse Brain 
Epilepsia  2007;48(Suppl 4):75-81.
Summary
Naturally occurring mutants and genetically manipulated strains of mice are widely used to model a variety of human diseases. Atlases are an invaluable aid in understanding the impact of such manipulations by providing a standard for comparison and to facilitate the integration of anatomic, genetic, and physiologic observations from multiple subjects and experiments. We have developed digital atlases of the C57BL/6J mouse brain (adult and neonate) as comprehensive frameworks for storing and accessing the myriad types of information about the mouse brain. Along with raw and annotated images, these contain database management systems and a set of tools for comparing information from different techniques and different animals. Each atlas establishes a canonical representation of the mouse brain and provides the tools for the manipulation and analysis of new data. We describe both these atlases and discuss how they may be put to use in organizing and analyzing data from mouse models of epilepsy.
doi:10.1111/j.1528-1167.2007.01244.x
PMCID: PMC3192853  PMID: 17767578
Anatomy; Atlas; Neonatal; Probabilistic
18.  The underlying anatomical correlates of long-term meditation: Larger hippocampal and frontal volumes of gray matter 
NeuroImage  2009;45(3):672-678.
Although the systematic study of meditation is still in its infancy, research has provided evidence for meditation-induced improvements in psychological and physiological well-being. Moreover, meditation practice has been shown not only to benefit higher-order cognitive functions but also to alter brain activity. Nevertheless, little is known about possible links to brain structure. Using high-resolution MRI data of 44 subjects, we set out to examine the underlying anatomical correlates of long-term meditation with different regional specificity (i.e., global, regional, and local). For this purpose, we applied voxel-based morphometry in association with a recently validated automated parcellation approach. We detected significantly larger gray matter volumes in meditators in the right orbito-frontal cortex (as well as in the right thalamus and left inferior temporal gyrus when co-varying for age and/or lowering applied statistical thresholds). In addition, meditators showed significantly larger volumes of the right hippocampus. Both orbito-frontal and hippocampal regions have been implicated in emotional regulation and response control. Thus, larger volumes in these regions might account for meditators’ singular abilities and habits to cultivate positive emotions, retain emotional stability, and engage in mindful behavior. We further suggest that these regional alterations in brain structures constitute part of the underlying neurological correlate of long-term meditation independent of a specific style and practice. Future longitudinal analyses are necessary to establish the presence and direction of a causal link between meditation practice and brain anatomy.
PMCID: PMC3184843  PMID: 19280691
Thalamus; Orbital; Hippocampus; MRI; Plasticity; VBM
19.  When more is less: associations between corpus callosum size and handedness lateralization 
NeuroImage  2010;52(1):43-49.
Although not consistently replicated, a substantial number of studies suggest that left-handers have larger callosal regions than right-handers. We challenge this notion and propose that callosal size is not linked to left-handedness or right-handedness per se but to the degree of handedness lateralization. To test this hypothesis, we investigated the thickness of the corpus callosum in a large data set (n=361). We analyzed the correlations between callosal thickness and the degree of handedness lateralization in 324 right-handers and 37 left-handers at 100 equidistant points across the corpus callosum. We revealed significant negative correlations within the anterior and posterior midbody suggesting that larger callosal dimensions in these regions are associated with a weaker handedness lateralization. Significant positive correlations were completely absent. In addition, we compared callosal thickness between moderately lateralized left-handers (n=37) and three equally sized groups (n=37) of right-handers (strongly, moderately, and weakly lateralized). The outcomes of these group analyses confirmed the negative association between callosal size and handedness lateralization, although callosal differences between right- and left-handers did not reach statistical significance. This suggests that callosal differences are rather small, if examined as a dichotomy between two handedness groups. Future studies will expand this line of research by increasing the number of left-handers to boost statistical power, and by combining macro- and micro-structural, as well as functional and behavioral measurements to identify the biological mechanisms linking callosal morphology and handedness lateralization.
doi:10.1016/j.neuroimage.2010.04.016
PMCID: PMC2903194  PMID: 20394828
corpus callosum; lateralization; handedness; MRI
20.  Neurobehavioral comorbidities of pediatric epilepsies are linked to thalamic structural abnormalities 
Epilepsia  2013;54(12):2116-2124.
Summary
Purpose
Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomical underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the combordities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes.
Methods
We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N= 21), CAE (N=20), and HC (N=27). Study subjects underwent structural MRI, intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, IQ, language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC.
Results
Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction.
Significance
Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy.
doi:10.1111/epi.12428
PMCID: PMC4259153  PMID: 24304435
21.  Why Sex Matters: Brain Size Independent Differences in Gray Matter Distributions between Men and Women 
The different brain anatomy of men and women is both a classic and continuing topic of major interest. Among the most replicated and robust sex differences are larger overall brain dimensions in men, and relative increases of global and regional gray matter (GM) in women. However, the question remains whether sex-typical differences in brain size (i.e., larger male and smaller female brains) or biological sex itself account for the observed sex effects on tissue amount and distribution. Exploring cerebral structures in men and women with similar brain size may clarify the true contribution of biological sex. We thus examined a sample of 24 male and 24 female subjects with brains identical in size, in addition to 24 male and 24 female subjects with considerable brain size differences. Using this large set of brains (n=96), we applied a well-validated and automated voxel-based approach to examine regional volumes of GM. While we revealed significant main effects of sex, there were no significant effects of brain size (and no significant interactions between sex and brain size). When conducting post hoc tests, we revealed a number of regions where women had larger GM volumes compared to men. Importantly, these sex effects remained evident when comparing men and women with the same brain size. Altogether, our findings suggest that the observed increased regional GM volumes in female brains constitute sex-dependent redistributions of tissue volume, rather than individual adjustments attributable to brain size.
doi:10.1523/JNEUROSCI.2261-09.2009
PMCID: PMC3110817  PMID: 19906974
Female; Gender; Male; MRI; TBV; VBM
22.  Digital reconstruction and morphometric analysis of human brain arterial vasculature from magnetic resonance angiography 
NeuroImage  2013;82:170-181.
Characterization of the complex branching architecture of cerebral arteries across a representative sample of the human population is important for diagnosing, analyzing, and predicting pathological states. Brain arterial vasculature can be visualized by magnetic resonance angiography (MRA). However, most MRA studies are limited to qualitative assessments, partial morphometric analyses, individual (or small numbers of) subjects, proprietary datasets, or combinations of the above limitations. Neuroinformatics tools, developed for neuronal arbor analysis, were used to quantify vascular morphology from 3 T time-of-flight MRA high-resolution (620 μm isotropic) images collected in 61 healthy volunteers (36/25 F/M, average age = 31.2 ± 10.7, range = 19–64 years). We present in-depth morphometric analyses of the global and local anatomical features of these arbors. The overall structure and size of the vasculature did not significantly differ across genders, ages, or hemispheres. The total length of the three major arterial trees stemming from the circle of Willis (from smallest to largest: the posterior, anterior, and middle cerebral arteries; or PCAs, ACAs, and MCAs, respectively) followed an approximate 1:2:4 proportion. Arterial size co-varied across individuals: subjects with one artery longer than average tended to have all other arteries also longer than average. There was no net right–left difference across the population in any of the individual arteries, but ACAs were more lateralized than MCAs. MCAs, ACAs, and PCAs had similar branch-level properties such as bifurcation angles. Throughout the arterial vasculature, there were considerable differences between branch types: bifurcating branches were significantly shorter and straighter than terminating branches. Furthermore, the length and meandering of bifurcating branches increased with age and with path distance from the circle of Willis. All reconstructions are freely distributed through a public database to enable additional analyses and modeling (cng.gmu.edu/brava).
doi:10.1016/j.neuroimage.2013.05.089
PMCID: PMC3971907  PMID: 23727319
23.  Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults 
NeuroImage  2013;82:146-153.
The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3′-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults related to genetic variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain.
To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 ± 2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) – a DTI measure of white matter integrity.
FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p = 0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders.
doi:10.1016/j.neuroimage.2013.05.095
PMCID: PMC3948328  PMID: 23727532
Fractional anisotropy; diffusion tensor imaging; single nucleotide polymorphism; schizophrenia; obsessive compulsive disorder; bipolar disorder
24.  TRACTOGRAPHY DENSITY AND NETWORK MEASURES IN ALZHEIMER’S DISEASE 
Brain connectivity declines in Alzheimer’s disease (AD), both functionally and structurally. Connectivity maps and networks derived from diffusion-based tractography offer new ways to track disease progression and to understand how AD affects the brain. Here we set out to identify (1) which fiber network measures show greatest differences between AD patients and controls, and (2) how these effects depend on the density of fibers extracted by the tractography algorithm. We computed brain networks from diffusion-weighted images (DWI) of the brain, in 110 subjects (28 normal elderly, 56 with early and 11 with late mild cognitive impairment, and 15 with AD). We derived connectivity matrices and network topology measures, for each subject, from whole-brain tractography and cortical parcellations. We used an ODF lookup table to speed up fiber extraction, and to exploit the full information in the orientation distribution function (ODF). This made it feasible to compute high density connectivity maps. We used accelerated tractography to compute a large number of fibers to understand what effect fiber density has on network measures and in distinguishing different disease groups in our data. We focused on global efficiency, transitivity, path length, mean degree, density, modularity, small world, and assortativity measures computed from weighted and binary undirected connectivity matrices. Of all these measures, the mean nodal degree best distinguished diagnostic groups. High-density fiber matrices were most helpful for picking up the more subtle clinical differences, e.g. between mild cognitively impaired (MCI) and normals, or for distinguishing subtypes of MCI (early versus late). Care is needed in clinical analyses of brain connectivity, as the density of extracted fibers may affect how well a network measure can pick up differences between patients and controls.
doi:10.1109/ISBI.2013.6556569
PMCID: PMC4232938  PMID: 25404994
tractography; Hadoop; MapReduce; network measures; connectivity matrix; Alzheimer’s disease; ODF
25.  LEFT VERSUS RIGHT HEMISPHERE DIFFERENCES IN BRAIN CONNECTIVITY: 4-TESLA HARDI TRACTOGRAPHY IN 569 TWINS 
Diffusion imaging can map anatomical connectivity in the living brain, offering new insights into fundamental questions such as how the left and right brain hemispheres differ. Anatomical brain asymmetries are related to speech and language abilities, but less is known about left/right hemisphere differences in brain wiring. To assess this, we scanned 457 young adults (age 23.4±2.0 SD years) and 112 adolescents (age 12-16) with 4-Tesla 105-gradient high-angular resolution diffusion imaging. We extracted fiber tracts throughout the brain with a Hough transform method. A 70×70 connectivity matrix was created, for each subject, based on the proportion of fibers intersecting 70 cortical regions. We identified significant differences in the proportions of fibers intersecting left and right hemisphere cortical regions. The degree of asymmetry in the connectivity matrices varied with age, as did the asymmetry in network topology measures such as the small-world effect.
doi:10.1109/ISBI.2012.6235601
PMCID: PMC4232939  PMID: 25404993
tractography; high angular resolution diffusion imaging (HARDI); small-world effect; connectome; laterality

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