A tensor-based morphometry study of genetic influences on brain structure using a new fluid registration method

We incorporated a new Riemannian fluid registration algorithm into a general MRI analysis method called tensor-based morphometry to map the heritability of brain morphology in MR images from 23 monozygotic and 23 dizygotic twin pairs. All 92 3D scans were fluidly registered to a common template. Voxelwise Jacobian determinants were computed from the deformation fields to assess local volumetric differences across subjects. Heritability maps were computed from the intraclass correlations and their significance was assessed using voxelwise permutation tests. Lobar volume heritability was also studied using the ACE genetic model. The performance of this Riemannian algorithm was compared to a more standard fluid registration algorithm: 3D maps from both registration techniques displayed similar heritability patterns throughout the brain. Power improvements were quantified by comparing the cumulative distribution functions of the p-values generated from both competing methods. The Riemannian algorithm outperformed the standard fluid registration.

Statistically assisted fluid registration algorithm - SAFIRA

In this paper, we develop and validate a new Statistically Assisted Fluid Registration Algorithm (SAFIRA) for brain images. A non-statistical version of this algorithm was first implemented in [2] and re-formulated using Lagrangian mechanics in [3]. Here we extend this algorithm to 3D: given 3D brain images from a population, vector fields and their corresponding deformation matrices are computed in a first round of registrations using the non-statistical implementation. Covariance matrices for both the deformation matrices and the vector fields are then obtained and incorporated (separately or jointly) in the regularizing (i.e., the non-conservative Lagrangian) terms, creating four versions of the algorithm. We evaluated the accuracy of each algorithm variant using the manually labeled LPBA40 dataset, which provides us with ground truth anatomical segmentations. We also compared the power of the different algorithms using tensor-based morphometry -a technique to analyze local volumetric differences in brain structure- applied to 46 3D brain scans from healthy monozygotic twins.

A nonconservative Lagrangian framework for statistical fluid registration - SAFIRA

In this paper, we used a nonconservative Lagrangian mechanics approach to formulate a new statistical algorithm for fluid registration of 3-D brain images. This algorithm is named SAFIRA, acronym for statistically-assisted fluid image registration algorithm. A nonstatistical version of this algorithm was implemented, where the deformation was regularized by penalizing deviations from a zero rate of strain. In, the terms regularizing the deformation included the covariance of the deformation matrices Σ and the vector fields (q). Here, we used a Lagrangian framework to reformulate this algorithm, showing that the regularizing terms essentially allow nonconservative work to occur during the flow. Given 3-D brain images from a group of subjects, vector fields and their corresponding deformation matrices are computed in a first round of registrations using the nonstatistical implementation. Covariance matrices for both the deformation matrices and the vector fields are then obtained and incorporated (separately or jointly) in the nonconservative terms, creating four versions of SAFIRA. We evaluated and compared our algorithms' performance on 92 3-D brain scans from healthy monozygotic and dizygotic twins; 2-D validations are also shown for corpus callosum shapes delineated at midline in the same subjects. After preliminary tests to demonstrate each method, we compared their detection power using tensor-based morphometry (TBM), a technique to analyze local volumetric differences in brain structure. We compared the accuracy of each algorithm variant using various statistical metrics derived from the images and deformation fields. All these tests were also run with a traditional fluid method, which has been quite widely used in TBM studies. The versions incorporating vector-based empirical statistics on brain variation were consistently more accurate than their counterparts, when used for automated volumetric quantification in new brain images. This suggests the advantages of this approach for large-scale neuroimaging studies.

Mapping the regional influence of genetics on brain structure variability - A Tensor-Based Morphometry study

Genetic and environmental factors influence brain structure and function profoundly. The search for heritable anatomical features and their influencing genes would be accelerated with detailed 3D maps showing the degree to which brain morphometry is genetically determined. As part of an MRI study that will scan 1150 twins, we applied Tensor-Based Morphometry to compute morphometric differences in 23 pairs of identical twins and 23 pairs of same-sex fraternal twins (mean age: 23.8 ± 1.8 SD years). All 92 twins' 3D brain MRI scans were nonlinearly registered to a common space using a Riemannian fluid-based warping approach to compute volumetric differences across subjects. A multi-template method was used to improve volume quantification. Vector fields driving each subject's anatomy onto the common template were analyzed to create maps of local volumetric excesses and deficits relative to the standard template. Using a new structural equation modeling method, we computed the voxelwise proportion of variance in volumes attributable to additive (A) or dominant (D) genetic factors versus shared environmental (C) or unique environmental factors (E). The method was also applied to various anatomical regions of interest (ROIs). As hypothesized, the overall volumes of the brain, basal ganglia, thalamus, and each lobe were under strong genetic control; local white matter volumes were mostly controlled by common environment. After adjusting for individual differences in overall brain scale, genetic influences were still relatively high in the corpus callosum and in early-maturing brain regions such as the occipital lobes, while environmental influences were greater in frontal brain regions that have a more protracted maturational time-course.

Information-theoretic analysis of brain white matter fiber orientation distribution functions

We propose a new information-theoretic metric, the symmetric Kullback-Leibler divergence (sKL-divergence), to measure the difference between two water diffusivity profiles in high angular resolution diffusion imaging (HARDI). Water diffusivity profiles are modeled as probability density functions on the unit sphere, and the sKL-divergence is computed from a spherical harmonic series, which greatly reduces computational complexity. Adjustment of the orientation of diffusivity functions is essential when the image is being warped, so we propose a fast algorithm to determine the principal direction of diffusivity functions using principal component analysis (PCA). We compare sKL-divergence with other inner-product based cost functions using synthetic samples and real HARDI data, and show that the sKL-divergence is highly sensitive in detecting small differences between two diffusivity profiles and therefore shows promise for applications in the nonlinear registration and multisubject statistical analysis of HARDI data.

Improving fluid registration through white matter segmentation in a twin study design

Robust and automatic non-rigid registration depends on many parameters that have not yet been systematically explored. Here we determined how tissue classification influences non-linear fluid registration of brain MRI. Twin data is ideal for studying this question, as volumetric correlations between corresponding brain regions that are under genetic control should be higher in monozygotic twins (MZ) who share 100% of their genes when compared to dizygotic twins (DZ) who share half their genes on average. When these substructure volumes are quantified using tensor-based morphometry, improved registration can be defined based on which method gives higher MZ twin correlations when compared to DZs, as registration errors tend to deplete these correlations. In a study of 92 subjects, higher effect sizes were found in cumulative distribution functions derived from statistical maps when performing tissue classification before fluid registration, versus fluidly registering the raw images. This gives empirical evidence in favor of pre-segmenting images for tensor-based morphometry.

Brain activity during automatic semantic priming revealed by event-related functional magnetic resonance imaging

Semantic priming occurs when a subject is faster in recognising a target word when it is preceded by a related word compared to an unrelated word. The effect is attributed to automatic or controlled processing mechanisms elicited by short or long interstimulus intervals (ISIs) between primes and targets. We employed event-related functional magnetic resonance imaging (fMRI) to investigate blood oxygen level dependent (BOLD) responses associated with automatic semantic priming using an experimental design identical to that used in standard behavioural priming tasks. Prime-target semantic strength was manipulated by using lexical ambiguity primes (e.g., bank) and target words related to dominant or subordinate meaning of the ambiguity. Subjects made speeded lexical decisions (word/nonword) on dominant related, subordinate related, and unrelated word pairs presented randomly with a short ISI. The major finding was a pattern of reduced activity in middle temporal and inferior prefrontal regions for dominant versus unrelated and subordinate versus unrelated comparisons, respectively. These findings are consistent with both a dual process model of semantic priming and recent repetition priming data that suggest that reductions in BOLD responses represent neural priming associated with automatic semantic activation and implicate the left middle temporal cortex and inferior prefrontal cortex in more automatic aspects of semantic processing.

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.

Meeting the challenges of neuroimaging genetics

As research encompassing neuroimaging and genetics gains momentum, extraordinary information will be uncovered on the genetic architecture of the human brain. However, there are significant challenges to be addressed first. Not the least of these challenges is to accomplish the sample size necessary to detect subtle genetic influences on the morphometry and function of the healthy brain. Aside from sample size, image acquisition and analysis methods need to be refined in order to ensure optimum sensitivity to genetic and complementary environmental influences. Then there is the vexing issue of interpreting the resulting data. We describe how researchers from the east coast of Australia and the west coast of America have embarked upon a collaboration to meet these challenges using data currently being collected from a large-scale twin study, and offer some opinions about future directions in the field.

Prefrontal cortex involvement in selective letter generation: A functional magnetic resonance imaging study

Cerebral responses to alternating periods of a control task and a selective letter generation paradigm were investigated with functional Magnetic Resonance Imaging (fMRI). Subjects selectively generated letters from four designated sets of six letters from the English language alphabet, with the instruction that they were not to produce letters in alphabetical order either forward or backward, repeat or alternate letters. Performance during this condition was compared with that of a control condition in which subjects recited the same letters in alphabetical order. Analyses revealed significant and extensive foci of activation in a number of cerebral regions including mid-dorsolateral frontal cortex, inferior frontal gyrus, precuneus, supramarginal gyrus, and cerebellum during the selective letter generation condition. These findings are discussed with respect to recent positron emission tomography (PET) and fMRI studies of verbal working memory and encoding/retrieval in episodic memory.

Changes in anatomical brain connectivity between ages 12 and 30: A HARDI study of 467 adolescents and adults

Graph theory can be applied to matrices that represent the brain's anatomical connections, to better understand global properties of anatomical networks, such as their clustering, efficiency and "small-world" topology. Network analysis is popular in adult studies of connectivity, but only one study - in just 30 subjects - has examined how network measures change as the brain develops over this period. Here we assessed the developmental trajectory of graph theory metrics of structural brain connectivity in a cross-sectional study of 467 subjects, aged 12 to 30. We computed network measures from 70×70 connectivity matrices of fiber density generated using whole-brain tractography in 4-Tesla 105-gradient high angular resolution diffusion images (HARDI). We assessed global efficiency and modularity, and both age and age 2 effects were identified. HARDI-based connectivity maps are sensitive to the remodeling and refinement of structural brain connections as the human brain develops.

Development of the 'rich club' in brain connectivity networks from 438 adolescents & adults aged 12 to 30

The 'rich club' coefficient describes a phenomenon where a network's hubs (high-degree nodes) are on average more intensely interconnected than lower-degree nodes. Networks with rich clubs often have an efficient, higher-order organization, but we do not yet know how the rich club emerges in the living brain, or how it changes as our brain networks develop. Here we chart the developmental trajectory of the rich club in anatomical brain networks from 438 subjects aged 12-30. Cortical networks were constructed from 68×68 connectivity matrices of fiber density, using whole-brain tractography in 4-Tesla 105-gradient high angular resolution diffusion images (HARDI). The adult and younger cohorts had rich clubs that included different nodes; the rich club effect intensified with age. Rich-club organization is a sign of a network's efficiency and robustness. These concepts and findings may be advantageous for studying brain maturation and abnormal brain development.

Hierarchical topological network analysis of anatomical human brain connectivity and differences related to sex and kinship

Modern non-invasive brain imaging technologies, such as diffusion weighted magnetic resonance imaging (DWI), enable the mapping of neural fiber tracts in the white matter, providing a basis to reconstruct a detailed map of brain structural connectivity networks. Brain connectivity networks differ from random networks in their topology, which can be measured using small worldness, modularity, and high-degree nodes (hubs). Still, little is known about how individual differences in structural brain network properties relate to age, sex, or genetic differences. Recently, some groups have reported brain network biomarkers that enable differentiation among individuals, pairs of individuals, and groups of individuals. In addition to studying new topological features, here we provide a unifying general method to investigate topological brain networks and connectivity differences between individuals, pairs of individuals, and groups of individuals at several levels of the data hierarchy, while appropriately controlling false discovery rate (FDR) errors. We apply our new method to a large dataset of high quality brain connectivity networks obtained from High Angular Resolution Diffusion Imaging (HARDI) tractography in 303 young adult twins, siblings, and unrelated people. Our proposed approach can accurately classify brain connectivity networks based on sex (93% accuracy) and kinship (88.5% accuracy). We find statistically significant differences associated with sex and kinship both in the brain connectivity networks and in derived topological metrics, such as the clustering coefficient and the communicability matrix.

Alzheimer's disease risk gene, GAB2, is associated with regional brain volume differences in 755 young healthy twins

The development of late-onset Alzheimer's disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer's disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27- 1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer's disease.

Genome-wide interaction analysis reveals replicated epistatic effects on brain structure

The discovery of several genes that affect the risk for Alzheimer's disease ignited a worldwide search for single-nucleotide polymorphisms (SNPs), common genetic variants that affect the brain. Genome-wide search of all possible SNP-SNP interactions is challenging and rarely attempted because of the complexity of conducting approximately 1011 pairwise statistical tests. However, recent advances in machine learning, for example, iterative sure independence screening, make it possible to analyze data sets with vastly more predictors than observations. Using an implementation of the sure independence screening algorithm (called EPISIS), we performed a genome-wide interaction analysis testing all possible SNP-SNP interactions affecting regional brain volumes measured on magnetic resonance imaging and mapped using tensor-based morphometry. We identified a significant SNP-SNP interaction between rs1345203 and rs1213205 that explains 1.9% of the variance in temporal lobe volume. We mapped the whole brain, voxelwise effects of the interaction in the Alzheimer's Disease Neuroimaging Initiative data set and separately in an independent replication data set of healthy twins (Queensland Twin Imaging). Each additional loading in the interaction effect was associated with approximately 5% greater brain regional brain volume (a protective effect) in both Alzheimer's Disease Neuroimaging Initiative and Queensland Twin Imaging samples.