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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.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Purkinje Cell Loss in Experimental Autoimmune Encephalomyelitis 
NeuroImage  2009;48(4):637-651.
Gray matter atrophy observed by brain MRI is an important correlate to clinical disability and disease duration in multiple sclerosis. The objective of this study was to link brain atrophy visualized by neuroimaging to its underlying neuropathology using the MS model, experimental autoimmune encephalomyelitis (EAE). Volumetric changes in brains of EAE mice, as well as matched healthy normal controls, were quantified by collecting post-mortem high-resolution T2-weighted magnetic resonance microscopy and actively-stained magnetic resonance histology images. Anatomical delineations demonstrated a significant decrease in the volume of the whole cerebellum, cerebellar cortex, and molecular layer of the cerebellar cortex in EAE as compared to normal controls. The pro-apoptotic marker caspase-3 was detected in Purkinje cells and a significant decrease in Purkinje cell number was found in EAE. Cross modality and temporal correlations revealed a significant association between Purkinje cell loss on neuropathology and atrophy of the molecular layer of the cerebellar cortex by neuroimaging. These results demonstrate the power of using combined population atlasing and neuropathology approaches to discern novel insights underlying gray matter atrophy in animal models of neurodegenerative disease.
doi:10.1016/j.neuroimage.2009.06.073
PMCID: PMC2754586  PMID: 19589388
cerebellum; gray matter atrophy; mouse; MRI; multiple sclerosis
18.  Detecting Brain Growth Patterns in Normal Children using Tensor-Based Morphometry 
Human brain mapping  2009;30(1):209-219.
Previous magnetic resonance imaging (MRI)-based volumetric studies have shown age-related increases in the volume of total white matter and decreases in the volume of total gray matter of normal children. Recent adaptations of image analysis strategies enable the detection of human brain growth with improved spatial resolution. In this article, we further explore the spatio-temporal complexity of adolescent brain maturation with tensor-based morphometry. By utilizing a novel non-linear elastic intensity-based registration algorithm on the serial structural MRI scans of 13 healthy children, individual Jacobian growth maps are generated and then registered to a common anatomical space. Statistical analyses reveal significant tissue growth in cerebral white matter, contrasted with gray matter loss in parietal, temporal, and occipital lobe. In addition, a linear regression with age and gender suggests a slowing down of the growth rate in regions with the greatest white matter growth. We demonstrate that a tensor-based Jacobian map is a sensitive and reliable method to detect regional tissue changes during development.
doi:10.1002/hbm.20498
PMCID: PMC2975704  PMID: 18064588
brain development; Jacobian; longitudinal; MRI; nonlinear image registration; TBM
19.  Regional gray matter variation in male-to-female transsexualism 
NeuroImage  2009;46(4):904-907.
Gender identity—one's sense of being a man or a woman—is a fundamental perception experienced by all individuals that extends beyond biological sex. Yet, what contributes to our sense of gender remains uncertain. Since individuals who identify as transsexual report strong feelings of being the opposite sex and a belief that their sexual characteristics do not reflect their true gender, they constitute an invaluable model to understand the biological underpinnings of gender identity. We analyzed MRI data of 24 male-to-female (MTF) transsexuals not yet treated with cross-sex hormones in order to determine whether gray matter volumes in MTF transsexuals more closely resemble people who share their biological sex (30 control men), or people who share their gender identity (30 control women). Results revealed that regional gray matter variation in MTF transsexuals is more similar to the pattern found in men than in women. However, MTF transsexuals show a significantly larger volume of regional gray matter in the right putamen compared to men. These findings provide new evidence that transsexualism is associated with distinct cerebral pattern, which supports the assumption that brain anatomy plays a role in gender identity.
doi:10.1016/j.neuroimage.2009.03.048
PMCID: PMC2754583  PMID: 19341803
Brain; Gender Identity; MRI; Transgender; VBM
20.  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
21.  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
22.  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
23.  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
24.  Neuroanatomical Correlates of Intelligence 
Intelligence  2009;37(2):156-163.
With the advancement of image acquisition and analysis methods in recent decades, unique opportunities have emerged to study the neuroanatomical correlates of intelligence. Traditional approaches examining global measures have been complemented by insights from more regional analyses based on pre-defined areas. Newer state-of-the-art approaches have further enhanced our ability to localize the presence of correlations between cerebral characteristics and intelligence with high anatomic precision. These in vivo assessments have confirmed mainly positive correlations, suggesting that optimally increased brain regions are associated with better cognitive performance. Findings further suggest that the models proposed to explain the anatomical substrates of intelligence should address contributions from not only (pre)frontal regions, but also widely distributed networks throughout the whole brain.
doi:10.1016/j.intell.2008.07.002
PMCID: PMC2770698  PMID: 20160919
Brain; Cerebral Cortex; Corpus Callosum; MRI
25.  A Diffusion Tensor Imaging Tractography Algorithm Based on Navier-Stokes Fluid Mechanics 
We introduce a fluid mechanics based tractography method for estimating the most likely connection paths between points in diffusion tensor imaging (DTI) volumes. We customize the Navier-Stokes equations to include information from the diffusion tensor and simulate an artificial fluid flow through the DTI image volume. We then estimate the most likely connection paths between points in the DTI volume using a metric derived from the fluid velocity vector field. We validate our algorithm using digital DTI phantoms based on a helical shape. Our method segmented the structure of the phantom with less distortion than was produced using implementations of heat-based partial differential equation (PDE) and streamline based methods. In addition, our method was able to successfully segment divergent and crossing fiber geometries, closely following the ideal path through a digital helical phantom in the presence of multiple crossing tracts. To assess the performance of our algorithm on anatomical data, we applied our method to DTI volumes from normal human subjects. Our method produced paths that were consistent with both known anatomy and directionally encoded color (DEC) images of the DTI dataset.
doi:10.1109/TMI.2008.2004403
PMCID: PMC2770434  PMID: 19244007
Tractography; DTI; white matter; fluid mechanics

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