Molecular genetic investigation of mitochondrial dysfunction in relation to migraine susceptibility

The aim of this research was to assess the role of genetic variation in mitochondrial function and how this relates to migraine pathophysiology. Using our unique Norfolk Island population, a custom in-house next generation sequencing methodology was developed. This data for the first time showed that there is a molecular genetic link between mitochondrial dysfunction and migraine susceptibility. This work has provided the foundation for further studies aimed at utilising the identified markers in improved migraine diagnostic and therapeutic strategies.

A practical guide to terminology for kimberlite facies: A systematic progression from descriptive to genetic, including a pocket guide

Kimberlite terminology remains problematic because both descriptive and genetic terms are mixed together in most existing terminology schemes. In addition, many terms used in existing kimberlite terminology schemes are not used in mainstream volcanology, even though kimberlite bodies are commonly the remains of kimberlite volcanic vents and edifices. We build on our own recently published approach to kimberlite facies terminology, involving a systematic progression from descriptive to genetic. The scheme can be used for both coherent kimberlite (i.e. kimberlite that was emplaced without undergoing any fragmentation processes and therefore preserving coherent igneous textures) and fragmental kimberlites. The approach involves documentation of components, textures and assessing the degree and effects of alteration on both components and original emplacement textures. This allows a purely descriptive composite component, textural and compositional petrological rock or deposit name to be constructed first, free of any biases about emplacement setting and processes. Then important facies features such as depositional structures, contact relationships and setting are assessed, leading to a composite descriptive and genetic name for the facies or rock unit that summarises key descriptive characteristics, emplacement processes and setting. Flow charts summarising the key steps in developing a progressive descriptive to genetic terminology are provided for both coherent and fragmental facies/deposits/rock units. These can be copied and used in the field, or in conjunction with field (e.g. drill core observations) and petrographic data. Because the approach depends heavily on field scale observations, characteristics and process interpretations, only the first descriptive part is appropriate where only petrographic observations are being made. Where field scale observations are available the progression from developing descriptive to interpretative terminology can be used, especially where some petrographic data also becomes available.

A new approach to kimberlite facies terminology using a revised general approach to the nomenclature of all volcanic rocks and deposits: Descriptive to genetic

Although kimberlite pipes/bodies are usually the remains of volcanic vents, in-vent deposits, and subvolcanic intrusions, the terminology used for kimberlite rocks has largely developed independently of that used in mainstream volcanology. Existing kimberlite terminology is not descriptive and includes terms that are rarely used, used differently, and even not used at all in mainstream volcanology. In addition, kimberlite bodies are altered to varying degrees, making application of genetic terminology difficult because original components and depositional textures are commonly masked by alteration. This paper recommends an approach to the terminology for kimberlite rocks that is consistent with usage for other volcanic successions. In modern terrains the eruption and emplacement origins of deposits can often be readily deduced, but this is often not the case for old, variably altered and deformed rock successions. A staged approach is required whereby descriptive terminology is developed first, followed by application of genetic terminology once all features, including the effects of alteration on original texture and depositional features, together with contact relationships and setting, have been evaluated. Because many volcanic successions consist of both primary volcanic deposits as well as volcanic sediments, terminology must account for both possibilities.

Effects of resistance training on measures of muscular strength in people with Parkinson’s disease: A systematic review and meta-analysis

Objective The aim of this systematic review and meta-analysis was to determine the overall effect of resistance training (RT) on measures of muscular strength in people with Parkinson’s disease (PD). Methods Controlled trials with parallel-group-design were identified from computerized literature searching and citation tracking performed until August 2014. Two reviewers independently screened for eligibility and assessed the quality of the studies using the Cochrane risk-of-bias-tool. For each study, mean differences (MD) or standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for continuous outcomes based on between-group comparisons using post-intervention data. Subgroup analysis was conducted based on differences in study design. Results Nine studies met the inclusion criteria; all had a moderate to high risk of bias. Pooled data showed that knee extension, knee flexion and leg press strength were significantly greater in PD patients who undertook RT compared to control groups with or without interventions. Subgroups were: RT vs. control-without-intervention, RT vs. control-with-intervention, RT-with-other-form-of-exercise vs. control-without-intervention, RT-with-other-form-of-exercise vs. control-with-intervention. Pooled subgroup analysis showed that RT combined with aerobic/balance/stretching exercise resulted in significantly greater knee extension, knee flexion and leg press strength compared with no-intervention. Compared to treadmill or balance exercise it resulted in greater knee flexion, but not knee extension or leg press strength. RT alone resulted in greater knee extension and flexion strength compared to stretching, but not in greater leg press strength compared to no-intervention. Discussion Overall, the current evidence suggests that exercise interventions that contain RT may be effective in improving muscular strength in people with PD compared with no exercise. However, depending on muscle group and/or training dose, RT may not be superior to other exercise types. Interventions which combine RT with other exercise may be most effective. Findings should be interpreted with caution due to the relatively high risk of bias of most studies.

Structural identification of a laboratory-based steel through truss cantilevered bridge with suspended span using a layered genetic algorithm with patternsearch step (GAPS)

Structural identification (St-Id) can be considered as the process of updating a finite element (FE) model of a structural system to match the measured response of the structure. This paper presents the St-Id of a laboratory-based steel through-truss cantilevered bridge with suspended span. There are a total of 600 degrees of freedom (DOFs) in the superstructure plus additional DOFs in the substructure. The St-Id of the bridge model used the modal parameters from a preliminary modal test in the objective function of a global optimisation technique using a layered genetic algorithm with patternsearch step (GAPS). Each layer of the St-Id process involved grouping of the structural parameters into a number of updating parameters and running parallel optimisations. The number of updating parameters was increased at each layer of the process. In order to accelerate the optimisation and ensure improved diversity within the population, a patternsearch step was applied to the fittest individuals at the end of each generation of the GA. The GAPS process was able to replicate the mode shapes for the first two lateral sway modes and the first vertical bending mode to a high degree of accuracy and, to a lesser degree, the mode shape of the first lateral bending mode. The mode shape and frequency of the torsional mode did not match very well. The frequencies of the first lateral bending mode, the first longitudinal mode and the first vertical mode matched very well. The frequency of the first sway mode was lower and that of the second sway mode was higher than the true values, indicating a possible problem with the FE model. Improvements to the model and the St-Id process will be presented at the upcoming conference and compared to the results presented in this paper. These improvements will include the use of multiple FE models in a multi-layered, multi-solution, GAPS St-Id approach.

ACE Research Vignette 042: Nascent ventures’ surprising resistance to macroeconomic crisis

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international entrepreneurship researchers. This vignette, written by Professor Per Davidsson, reports findings on how the onset of the Global Financial Crisis affected “nascent ventures”, i.e., on-going business start-up efforts.

Genetic and environmental influences on neuroimaging phenotypes: A meta-analytical perspective on twin imaging studies

Because brain structure and function are affected in neurological and psychiatric disorders, it is important to disentangle the sources of variation in these phenotypes. Over the past 15 years, twin studies have found evidence for both genetic and environmental influences on neuroimaging phenotypes, but considerable variation across studies makes it difficult to draw clear conclusions about the relative magnitude of these influences. Here we performed the first meta-analysis of structural MRI data from 48 studies on >1,250 twin pairs, and diffusion tensor imaging data from 10 studies on 444 twin pairs. The proportion of total variance accounted for by genes (A), shared environment (C), and unshared environment (E), was calculated by averaging A, C, and E estimates across studies from independent twin cohorts and weighting by sample size. The results indicated that additive genetic estimates were significantly different from zero for all metaanalyzed phenotypes, with the exception of fractional anisotropy (FA) of the callosal splenium, and cortical thickness (CT) of the uncus, left parahippocampal gyrus, and insula. For many phenotypes there was also a significant influence of C. We now have good estimates of heritability for many regional and lobar CT measures, in addition to the global volumes. Confidence intervals are wide and number of individuals small for many of the other phenotypes. In conclusion, while our meta-analysis shows that imaging measures are strongly influenced by genes, and that novel phenotypes such as CT measures, FA measures, and brain activation measures look especially promising, replication across independent samples and demographic groups is necessary.

Genetic effects on the cerebellar role in working memory: Same brain, different genes?

Over the past several years, evidence has accumulated showing that the cerebellum plays a significant role in cognitive function. Here we show, in a large genetically informative twin sample (n= 430; aged 16-30. years), that the cerebellum is strongly, and reliably (n=30 rescans), activated during an n-back working memory task, particularly lobules I-IV, VIIa Crus I and II, IX and the vermis. Monozygotic twin correlations for cerebellar activation were generally much larger than dizygotic twin correlations, consistent with genetic influences. Structural equation models showed that up to 65% of the variance in cerebellar activation during working memory is genetic (averaging 34% across significant voxels), most prominently in the lobules VI, and VIIa Crus I, with the remaining variance explained by unique/unshared environmental factors. Heritability estimates for brain activation in the cerebellum agree with those found for working memory activation in the cerebral cortex, even though cerebellar cyto-architecture differs substantially. Phenotypic correlations between BOLD percent signal change in cerebrum and cerebellum were low, and bivariate modeling indicated that genetic influences on the cerebellum are at least partly specific to the cerebellum. Activation on the voxel-level correlated very weakly with cerebellar gray matter volume, suggesting specific genetic influences on the BOLD signal. Heritable signals identified here should facilitate discovery of genetic polymorphisms influencing cerebellar function through genome-wide association studies, to elucidate the genetic liability to brain disorders affecting the cerebellum.

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.

A new registration method based on Log-Euclidean tensor metrics and its application to genetic studies

In structural brain MRI, group differences or changes in brain structures can be detected using Tensor-Based Morphometry (TBM). This method consists of two steps: (1) a non-linear registration step, that aligns all of the images to a common template, and (2) a subsequent statistical analysis. The numerous registration methods that have recently been developed differ in their detection sensitivity when used for TBM, and detection power is paramount in epidemological studies or drug trials. We therefore developed a new fluid registration method that computes the mappings and performs statistics on them in a consistent way, providing a bridge between TBM registration and statistics. We used the Log-Euclidean framework to define a new regularizer that is a fluid extension of the Riemannian elasticity, which assures diffeomorphic transformations. This regularizer constrains the symmetrized Jacobian matrix, also called the deformation tensor. We applied our method to an MRI dataset from 40 fraternal and identical twins, to revealed voxelwise measures of average volumetric differences in brain structure for subjects with different degrees of genetic resemblance.

Extending genetic linkage analysis to diffusion tensor images to map single gene effects on brain fiber architecture

We extended genetic linkage analysis - an analysis widely used in quantitative genetics - to 3D images to analyze single gene effects on brain fiber architecture. We collected 4 Tesla diffusion tensor images (DTI) and genotype data from 258 healthy adult twins and their non-twin siblings. After high-dimensional fluid registration, at each voxel we estimated the genetic linkage between the single nucleotide polymorphism (SNP), Val66Met (dbSNP number rs6265), of the BDNF gene (brain-derived neurotrophic factor) with fractional anisotropy (FA) derived from each subject's DTI scan, by fitting structural equation models (SEM) from quantitative genetics. We also examined how image filtering affects the effect sizes for genetic linkage by examining how the overall significance of voxelwise effects varied with respect to full width at half maximum (FWHM) of the Gaussian smoothing applied to the FA images. Raw FA maps with no smoothing yielded the greatest sensitivity to detect gene effects, when corrected for multiple comparisons using the false discovery rate (FDR) procedure. The BDNF polymorphism significantly contributed to the variation in FA in the posterior cingulate gyrus, where it accounted for around 90-95% of the total variance in FA. Our study generated the first maps to visualize the effect of the BDNF gene on brain fiber integrity, suggesting that common genetic variants may strongly determine white matter integrity.

Mapping genetic influences on brain fiber architecture with high angular resolution diffusion imaging (HARDI)

We report the first 3D maps of genetic effects on brain fiber complexity. We analyzed HARDI brain imaging data from 90 young adult twins using an information-theoretic measure, the Jensen-Shannon divergence (JSD), to gauge the regional complexity of the white matter fiber orientation distribution functions (ODF). HARDI data were fluidly registered using Karcher means and ODF square-roots for interpol ation; each subject's JSD map was computed from the spatial coherence of the ODFs in each voxel's neighborhood. We evaluated the genetic influences on generalized fiber anisotropy (GFA) and complexity (JSD) using structural equation models (SEM). At each voxel, genetic and environmental components of data variation were estimated, and their goodness of fit tested by permutation. Color-coded maps revealed that the optimal models varied for different brain regions. Fiber complexity was predominantly under genetic control, and was higher in more highly anisotropic regions. These methods show promise for discovering factors affecting fiber connectivity in the brain.

Hierarchical clustering of the genetic connectivity matrix reveals the network topology of gene action on brain microstructure: An N=531 twin study

Genetic correlation (rg) analysis determines how much of the correlation between two measures is due to common genetic influences. In an analysis of 4 Tesla diffusion tensor images (DTI) from 531 healthy young adult twins and their siblings, we generalized the concept of genetic correlation to determine common genetic influences on white matter integrity, measured by fractional anisotropy (FA), at all points of the brain, yielding an NxN genetic correlation matrix rg(x,y) between FA values at all pairs of voxels in the brain. With hierarchical clustering, we identified brain regions with relatively homogeneous genetic determinants, to boost the power to identify causal single nucleotide polymorphisms (SNP). We applied genome-wide association (GWA) to assess associations between 529,497 SNPs and FA in clusters defined by hubs of the clustered genetic correlation matrix. We identified a network of genes, with a scale-free topology, that influences white matter integrity over multiple brain regions.

Quantitative genetic modeling of lateral ventricular shape and volume using multi-atlas fluid image alignment in twins

Despite substantial progress in measuring the 3D profile of anatomical variations in the human brain, their genetic and environmental causes remain enigmatic. We developed an automated system to identify and map genetic and environmental effects on brain structure in large brain MRI databases . We applied our multi-template segmentation approach ("Multi-Atlas Fluid Image Alignment") to fluidly propagate hand-labeled parameterized surface meshes into 116 scans of twins (60 identical, 56 fraternal), labeling the lateral ventricles. Mesh surfaces were averaged within subjects to minimize segmentation error. We fitted quantitative genetic models at each of 30,000 surface points to measure the proportion of shape variance attributable to (1) genetic differences among subjects, (2) environmental influences unique to each individual, and (3) shared environmental effects. Surface-based statistical maps revealed 3D heritability patterns, and their significance, with and without adjustments for global brain scale. These maps visualized detailed profiles of environmental versus genetic influences on the brain, extending genetic models to spatially detailed, automatically computed, 3D maps.

Mapping genetic influences on ventricular structure in twins

Despite substantial progress in measuring the anatomical and functional variability of the human brain, little is known about the genetic and environmental causes of these variations. Here we developed an automated system to visualize genetic and environmental effects on brain structure in large brain MRI databases. We applied our multi-template segmentation approach termed "Multi-Atlas Fluid Image Alignment" to fluidly propagate hand-labeled parameterized surface meshes, labeling the lateral ventricles, in 3D volumetric MRI scans of 76 identical (monozygotic, MZ) twins (38 pairs; mean age = 24.6 (SD = 1.7)); and 56 same-sex fraternal (dizygotic, DZ) twins (28 pairs; mean age = 23.0 (SD = 1.8)), scanned as part of a 5-year research study that will eventually study over 1000 subjects. Mesh surfaces were averaged within subjects to minimize segmentation error. We fitted quantitative genetic models at each of 30,000 surface points to measure the proportion of shape variance attributable to (1) genetic differences among subjects, (2) environmental influences unique to each individual, and (3) shared environmental effects. Surface-based statistical maps, derived from path analysis, revealed patterns of heritability, and their significance, in 3D. Path coefficients for the 'ACE' model that best fitted the data indicated significant contributions from genetic factors (A = 7.3%), common environment (C = 38.9%) and unique environment (E = 53.8%) to lateral ventricular volume. Earlier-maturing occipital horn regions may also be more genetically influenced than later-maturing frontal regions. Maps visualized spatially-varying profiles of environmental versus genetic influences. The approach shows promise for automatically measuring gene-environment effects in large image databases.