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.
Anatomical brain connectivity; Complex networks; Diffusion weighted MRI; Topological analysis; Hierarchical analysis; False discovery rate; Sex and kinship brain network differences
Diffusion tensor imaging (DTI) is sensitive to the directionally- constrained flow of water, which diffuses preferentially along axons. Tractography programs may be used to infer matrices of connectivity (anatomical networks) between pairs of brain regions. Little is known about how these computed connectivity measures depend on the scans’ spatial and angular resolutions. To determine this, we scanned 8 young adults with DTI at 2.5 and 3 mm resolutions, and an additional subject at 4 resolutions between 2–4 mm. We computed 70×70 connectivity matrices, using whole-brain tractography to measure fiber density between all pairs of 70 cortical and subcortical regions. Spatial and angular resolution affected the computed connectivity for narrower tracts (internal capsule and cerebellum), but also for the corticospinal tract. Data resolution affected the apparent role of some key structures in cortical anatomic networks. Care is needed when comparing network data across studies, and interpreting apparent disagreements among findings.
Connectivity; diffusion imaging; tractography; networks; MRI; brain
Penalized or sparse regression methods are gaining increasing attention in imaging genomics, as they can select optimal regressors from a large set of predictors whose individual effects are small or mostly zero. We applied a multivariate approach, based on L1-L2-regularized regression (elastic net) to predict a magnetic resonance imaging (MRI) tensor-based morphometry-derived measure of temporal lobe volume from a genome-wide scan in 740 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects. We tuned the elastic net model’s parameters using internal crossvalidation and evaluated the model on independent test sets. Compared to 100,000 permutations performed with randomized imaging measures, the predictions were found to be statistically significant (p ~ 0.001). The rs9933137 variant in the RBFOX1 gene was a highly contributory genotype, along with rs10845840 in GRIN2B and rs2456930, discovered previously in a univariate genomewide search.
Neuroimaging; MRI; Prediction; Elastic net; Imaging Genetics
Alzheimer’s Disease (AD) has long been considered a cortical degenerative disease, but impaired brain connectivity, due to white matter injury, may exacerbate cognitive problems. Predicting brain changes is critically important for early treatment. In a longitudinal diffusion tensor imaging study, we investigated white matter fiber integrity in 19 patients (mean age: 74.7 +/− 8.4 yrs at baseline) displaying early signs of mild cognitive impairment (eMCI). We first examined whether baseline average fractional anisotropy (FA) measures in the corpus callosum (CC) predicted changes in white matter integrity over the following 6 months. We then examined whether “small world” architecture measures - calculated from baseline connectivity maps - predicted white matter changes over the next 6 months. While average CC FA measures at baseline were not associated with future changes in FA, network measures were a sensitive biomarker for predicting white matter changes during this critical time before AD strikes.
diffusion imaging; graph theory; connectivity; predictive models; Alzheimer’s disease
Large multi-site image-analysis studies have successfully discovered genetic variants that affect brain structure in tens of thousands of subjects scanned worldwide. Candidate genes have also associated with brain integrity, measured using fractional anisotropy in diffusion tensor images (DTI). To evaluate the heritability and robustness of DTI measures as a target for genetic analysis, we compared 417 twins and siblings scanned on the same day on the same high field scanner (4-Tesla) with two protocols: (1) 94-directions; 2mm-thick slices, (2) 27-directions; 5mm-thickness. Using mean FA in white matter ROIs and FA ‘skeletons’ derived using FSL, we (1) examined differences in voxelwise means, variances, and correlations among the measures; and (2) assessed heritability with structural equation models, using the classical twin design. FA measures from the genu of the corpus callosum were highly heritable, regardless of protocol. Genome-wide analysis of the genu mean FA revealed differences across protocols in the top associations.
imaging genetics; DTI protocol stability; corpus callosum; genome-wide association study; multi-site analysis
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 age2 effects were identified. HARDI-based connectivity maps are sensitive to the remodeling and refinement of structural brain connections as the human brain develops.
graph theory; high angular resolution diffusion imaging (HARDI); tractography; network analyses; development; structural connectivity
Human brain connectivity is disrupted in a wide range of disorders – from Alzheimer’s disease to autism – but little is known about which specific genes affect it. Here we conducted a genome-wide association for connectivity matrices that capture information on the density of fiber connections between 70 brain regions. We scanned a large twin cohort (N=366) with 4-Tesla high angular resolution diffusion imaging (105-gradient HARDI). Using whole brain HARDI tractography, we extracted a relatively sparse 70×70 matrix representing fiber density between all pairs of cortical regions automatically labeled in co-registered anatomical scans. Additive genetic factors accounted for 1–58% of the variance in connectivity between 90 (of 122) tested nodes. We discovered genome-wide significant associations between variants and connectivity. GWAS permutations at various levels of heritability, and split-sample replication, validated our genetic findings. The resulting genes may offer new leads for mechanisms influencing aberrant connectivity and neurodegeneration.
genetics; high angular resolution diffusion imaging (HARDI); cortical surfaces; twin modeling; human connectome
The NTRK1 gene (also known as TRKA) encodes a high affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower FA in healthy adults.
We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 Tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy – a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test results reproducibility. The false discovery rate method corrected for voxelwise multiple comparisons.
NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure.
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.
structural connectivity; HARDI; autism; CNTNAP2; graph theory; twins
A global probabilistic fiber tracking approach based on the voting process provided by the Hough transform is introduced in this work. The proposed framework tests candidate 3D curves in the volume, assigning to each one a score computed from the diffusion images, and then selects the curves with the highest scores as the potential anatomical connections. The algorithm avoids local minima by performing an exhaustive search at the desired resolution. The technique is easily extended to multiple subjects, considering a single representative volume where the registered high-angular resolution diffusion images (HARDI) from all the subjects are non-linearly combined, thereby obtaining population-representative tracts. The tractography algorithm is run only once for the multiple subjects, and no tract alignment is necessary. We present experimental results on HARDI volumes, ranging from simulated and 1.5T physical phantoms to 7T and 4T human brain and 7T monkey brain datasets.
Tractography; diffusion-weighted magnetic resonance imaging (DWI); Hough transform; orientation distribution function (ODF); population studies
Imaging traits provide a powerful and biologically relevant substrate to examine the influence of genetics on the brain. Interest in genome-wide, brain-wide search for influential genetic variants is growing, but has mainly focused on univariate, SNP-based association tests. Moving to gene-based multivariate statistics, we can test the combined effect of multiple genetic variants in a single test statistic. Multivariate models can reduce the number of statistical tests in gene-wide or genome-wide scans and may discover gene effects undetectable with SNP-based methods. Here we present a gene-based method for associating the joint effect of single nucleotide polymorphisms (SNPs) in 18,044 genes across 31,662 voxels of the whole brain in 731 elderly subjects (mean age: 75.56 ± 6.82SD years; 430 males) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Structural MRI scans were analyzed using tensor-based morphometry (TBM) to compute 3D maps of regional brain volume differences compared to an average template image based on healthy elderly subjects. Using the voxel-level volume difference values as the phenotype, we selected the most significantly associated gene (out of 18,044) at each voxel across the brain. No genes identified were significant after correction for multiple comparisons, but several known candidates were re-identified, as were other genes highly relevant to brain function. GAB2, which has been previously associated with late-onset AD, was identified as the top gene in this study, suggesting the validity of the approach. This multivariate, gene-based voxelwise association study offers a novel framework to detect genetic influences on the brain.
principal components regression; voxelwise; multivariate; gene-based; GWAS; GAB2 (max. 6 keywords)
We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2. We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8 ± 2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain.
neuroimaging; MRI; imaging genetics; GWAS; LASSO; MACROD2
There is a strong genetic risk for late-onset Alzheimer’s disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by approximately 88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset.
We scanned 398 healthy young adults (mean age 23.6 ± 2.2 years) with diffusion tensor imaging (DTI), a variation of magnetic resonance imaging (MRI) sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed model regression at each point in the brain to map the profile of these associations with white matter integrity.
Each C allele copy of the CLU variant was associated with lower fractional anisotropy (FA) - a widely accepted measure of white matter integrity- in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres.
Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.
Clusterin; white matter; diffusion tensor imaging; fractional anisotropy; MRI; splenium
Brain asymmetry, or the structural and functional specialization of each brain hemisphere, has fascinated neuroscientists for over a century. Even so, genetic and environmental factors that influence brain asymmetry are largely unknown. Diffusion tensor imaging (DTI) now allows asymmetry to be studied at a microscopic scale by examining differences in fiber characteristics across hemispheres rather than differences in structure shapes and volumes. Here we analyzed 4 Tesla DTI scans from 374 healthy adults, including 60 monozygotic twin pairs, 45 same-sex dizygotic pairs, and 164 mixed-sex DZ twins and their siblings; mean age: 24.4 years +/− 1.9SD). All DTI scans were nonlinearly aligned to a geometrically-symmetric, population-based image template. We computed voxel-wise maps of significant asymmetries (left/right differences) for common diffusion measures that reflect fiber integrity (fractional and geodesic anisotropy; FA, GA and mean diffusivity, MD). In quantitative genetic models computed from all same-sex twin pairs (N=210 subjects), genetic factors accounted for 33% of the variance in asymmetry for the inferior fronto-occipital fasciculus, 37% for the anterior thalamic radiation, and 20% for the forceps major and uncinate fasciculus (all L>R). Shared environmental factors accounted for around 15% of the variance in asymmetry for the cortico-spinal tract (R>L) and about 10% for the forceps minor (L>R). Sex differences in asymmetry (men > women) were significant, and were greatest in regions with prominent FA asymmetries. These maps identify heritable DTI-derived features, and may empower genome-wide searches for genetic polymorphisms that influence brain asymmetry.
DTI; brain asymmetry; fractional anisotropy; geodesic anisotropy; structural equation model; twins; quantitative genetics; path analysis
A key question in diffusion imaging is how many diffusion-weighted images suffice to provide adequate signal-to-noise ratio (SNR) for studies of fiber integrity. Motion, physiological effects, and scan duration all affect the achievable SNR in real brain images, making theoretical studies and simulations only partially useful. We therefore scanned 50 healthy adults with 105-gradient high-angular resolution diffusion imaging (HARDI) at 4 Tesla. From gradient image subsets of varying size (6≤N≤94) that optimized a spherical angular distribution energy, we created SNR plots (versus gradient numbers) for seven common diffusion anisotropy indices: fractional and relative anisotropy (FA, RA), mean diffusivity (MD), volume ratio (VR), geodesic anisotropy (GA), its hyperbolic tangent (tGA), and generalized fractional anisotropy (GFA). SNR, defined in a region of interest in the corpus callosum, was near-maximal with 58, 66 and 62 gradients for MD, FA and RA in respectively, and with about 55 gradients for GA and tGA. For VR and GFA, SNR increased rapidly with more gradients. SNR was optimized when the ratio of diffusion-sensitized to non-sensitized images was 9.13 for GA and tGA, 10.57 for FA, 9.17 for RA, and 26 for MD and VR. In orientation density functions modeling the HARDI signal as a continuous mixture of tensors, the diffusion profile reconstruction accuracy rose rapidly with additional gradients. These plots may help in making trade-off decisions when designing diffusion imaging protocols.
High-Angular Resolution Diffusion imaging; anisotropic scalar; generalized fractional anisotropy; tensor; Signal-to-Noise ratio; Kullback-Leibler divergence
Mouse models of human diseases play crucial roles in understanding disease mechanisms and developing therapeutic measures. Huntington’s disease (HD) is characterized by striatal atrophy that begins long before the onset of motor symptoms. In symptomatic HD, striatal volumes decline predictably with disease course. Thus, imaging based volumetric measures have been proposed as outcomes for presymptomatic as well as symptomatic clinical trials of HD. Magnetic resonance imaging of the mouse brain structures is becoming widely available and has been proposed as one of the biomarkers of disease progression and drug efficacy testing. However, three-dimensional and quantitative morphological analyses of the brains are not straightforward. In this paper, we describe a tool for automated segmentation and voxel-based morphological analyses of the mouse brains. This tool was applied to a well-established mouse model of Huntington disease, the R6/2 transgenic mouse strain. Comparison between the automated and manual segmentation results showed excellent agreement in most brain regions. The automated method was able to sensitively detect atrophy as early as 3 weeks of age and accurately follow disease progression. Comparison between ex vivo and in vivo MRI suggests that the ex vivo end-point measurement of brain morphology is also a valid approach except for the morphology of the ventricles. This is the first report of longitudinal characterization of brain atrophy in a mouse model of Huntington’s disease by using automatic morphological analysis.
Huntington’s disease; MRI; brain atrophy; biomarker; automated morphological analysis
A patient’s electronic medical record can consist of a large number of reports, especially for an elderly patient or for one affected by a chronic disease. It can thus be cumbersome for a physician to go through all of the reports to understand the patient’s complete medical history. This paper describes work in progress towards tracking medications and their dosages through the course of a patient’s medical history. 923 reports associated with 11 patients were obtained from a university hospital. Drug names were identified using a dictionary look-up approach. Dosages corresponding to these drugs were determined using regular expressions. The state of a drug (ON, OFF), which determines whether or not the drug was being taken, was identified using a support vector machine with features based on expert knowledge. Results were promising: prec. ≈ recall ≈ 87%. The output is a timeline display of the drugs which the patient has been taking.