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.

Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease

We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles in brain MRI scans, providing an efficient approach to monitor degenerative disease in clinical studies and drug trials. First, we used a set of parameterized surfaces to represent the ventricles in four subjects' manually labeled brain MRI scans (atlases). We fluidly registered each atlas and mesh model to MRIs from 17 Alzheimer's disease (AD) patients and 13 age- and gender-matched healthy elderly control subjects, and 18 asymptomatic ApoE4-carriers and 18 age- and gender-matched non-carriers. We examined genotyped healthy subjects with the goal of detecting subtle effects of a gene that confers heightened risk for Alzheimer's disease. We averaged the meshes extracted for each 3D MR data set, and combined the automated segmentations with a radial mapping approach to localize ventricular shape differences in patients. Validation experiments comparing automated and expert manual segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease- and gene-related alterations improved, as the number of atlases, N, was increased from 1 to 9. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases. We formulated a statistical stopping criterion to determine the optimal number of atlases to use. Healthy ApoE4-carriers and those with AD showed local ventricular abnormalities. This high-throughput method for morphometric studies further motivates the combination of genetic and neuroimaging strategies in predicting AD progression and treatment response. © 2007 Elsevier Inc. All rights reserved.

Automated 3D mapping & shape analysis of the lateral ventricles via fluid registration of multiple surface-based atlases

We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles, designed for monitoring degenerative disease effects in clinical neuroscience studies and drug trials. First we used a set of parameterized surfaces to represent the ventricles in a manually labeled set of 9 subjects' MRIs (atlases). We fluidly registered each of these atlases and mesh models to a set of MRIs from 12 Alzheimer's disease (AD) patients and 14 matched healthy elderly subjects, and we averaged the resulting meshes for each of these images. Validation experiments on expert segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease-related alterations monotonically improved as the number of atlases, N, was increased from 1 to 9. We then combined the segmentations with a radial mapping approach to localize ventricular shape differences in patients. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases, and we formulated a statistical stopping criterion to determine the optimal value of N. Anterior horn anomalies in Alzheimer's patients were only detected with the multi-atlas segmentation, which clearly outperformed the standard single-atlas approach.

Direct mapping of hippocampal surfaces with intrinsic shape context

We propose in this paper a new method for the mapping of hippocampal (HC) surfaces to establish correspondences between points on HC surfaces and enable localized HC shape analysis. A novel geometric feature, the intrinsic shape context, is defined to capture the global characteristics of the HC shapes. Based on this intrinsic feature, an automatic algorithm is developed to detect a set of landmark curves that are stable across population. The direct map between a source and target HC surface is then solved as the minimizer of a harmonic energy function defined on the source surface with landmark constraints. For numerical solutions, we compute the map with the approach of solving partial differential equations on implicit surfaces. The direct mapping method has the following properties: (1) it has the advantage of being automatic; (2) it is invariant to the pose of HC shapes. In our experiments, we apply the direct mapping method to study temporal changes of HC asymmetry in Alzheimer's disease (AD) using HC surfaces from 12 AD patients and 14 normal controls. Our results show that the AD group has a different trend in temporal changes of HC asymmetry than the group of normal controls. We also demonstrate the flexibility of the direct mapping method by applying it to construct spherical maps of HC surfaces. Spherical harmonics (SPHARM) analysis is then applied and it confirms our results on temporal changes of HC asymmetry in AD.

Mapping hippocampal and ventricular change in Alzheimer disease

We developed an anatomical mapping technique to detect hippocampal and ventricular changes in Alzheimer disease (AD). The resulting maps are sensitive to longitudinal changes in brain structure as the disease progresses. An anatomical surface modeling approach was combined with surface-based statistics to visualize the region and rate of atrophy in serial MRI scans and isolate where these changes link with cognitive decline. Fifty-two high-resolution MRI scans were acquired from 12 AD patients (age: 68.4 ± 1.9 years) and 14 matched controls (age: 71.4 ± 0.9 years), each scanned twice (2.1 ± 0.4 years apart). 3D parametric mesh models of the hippocampus and temporal horns were created in sequential scans and averaged across subjects to identify systematic patterns of atrophy. As an index of radial atrophy, 3D distance fields were generated relating each anatomical surface point to a medial curve threading down the medial axis of each structure. Hippocampal atrophic rates and ventricular expansion were assessed statistically using surface-based permutation testing and were faster in AD than in controls. Using color-coded maps and video sequences, these changes were visualized as they progressed anatomically over time. Additional maps localized regions where atrophic changes linked with cognitive decline. Temporal horn expansion maps were more sensitive to AD progression than maps of hippocampal atrophy, but both maps correlated with clinical deterioration. These quantitative, dynamic visualizations of hippocampal atrophy and ventricular expansion rates in aging and AD may provide a promising measure to track AD progression in drug trials.

Corrigendum to "Mapping hippocampal and ventricular change in Alzheimer disease" [NeuroImage 22 (2004) 1754-1766] (DOI:10.1016/j.neuroimage.2004.03.040)

We recently noticed an error in the demographic data in this article. The validity of the findings and the conclusions of the paper is not affected. However, there is an error in the reported sample size and in the means and standard deviations of the subjects’ ages and MMSE scores. We would like to correct this error, which came to light when we were re-analyzing the data for a meta-analysis. The error occurred because an older version of a spreadsheet was incorrectly used when reporting the sample composition. Instead of examining 12 Alzheimer's disease patients and 14 healthy elderly controls, we in fact examined 17 Alzheimer’s disease patients and 14 healthy elderly controls. All maps and morphometric data reported in the paper are correct, except that the sample size was in fact slightly higher than that originally reported, and the maps computed in the paper were based on the larger sample (which included five more subjects in the Alzheimer’s disease group). All of the maps and figures in the paper are correct, and the conclusions of the paper are unchanged. We apologize for this error, which falls under the sole responsibility of the first author. The corrected demographic information appears below.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

Can biophilic urbanism deliver strong economic and social benefits in cities? An economic and policy invetigations into the increased use of natural elements in urban design

Biophilic urbanism, or urban design that reflects humanity’s innate need for nature, stands to make significant contributions to a range of national, state and local government policies related to climate change mitigation and adaptation, by investigating ways in which nature can be integrated into, around and on top of buildings. Potential benefits of such design include reducing the heat island effect, reducing energy consumption for thermal control, enhancing urban biodiversity, improving well being and productivity, improving water cycle management, and assisting in the response to growing needs for densification and revitalisation of cities. This report will give an overview of the concept of biophilia and consider enablers and disablers to its application to urban planning and design. The paper will present findings from stakeholder engagement and a series of detailed case studies, related to a consideration of the economics of the use of biophilic elements (direct and indirect).

The dynamics of global visual effects and games development industries: lessons for Australia’s creative industries development policy

The paper critiques the focus of creative industries policy on capability development of small and medium sized firms and the provision of regional incentives. It analyses factors affecting the competitiveness and sustainability of the games development industry and visual effects suppliers to feature films. Interviews with participants in these industries highlight the need for policy instruments to take into consideration the structure and organization of global markets and the power of lead multinational corporations. We show that although forms of economic governance in these industries may allow sustainable value capture, they are interrupted by bottlenecks in which ferocious competition among suppliers is confronted by comparatively little competition among the lead firms. We argue that current approaches to creative industries policy aimed at building self-sustaining creative industries are unlikely to be sufficient because of the globalized nature of the industries. Rather, we argue that a more profitable approach is likely to require supporting diversification of the industries as ‘feeders’ into other areas of the economy.

The alchemy of junk: patent law and non-coding DNA

This article considers the recent international controversy over the patents held by a Melbourne firm, Genetic Technologies Limited (GTG), in respect of non-coding DNA and genomic mapping. It explores the ramifications of the GTG dispute in terms of licensing, litigation, and policy reform, and—as a result of this dispute—the perceived conflict between law and science. GTG has embarked upon an ambitious licensing program with twenty seven commercial licensees and five research licensees. Most significantly, GTG has obtained an exclusive licence from Myriad Genetics to use and exploit its medical diagnostics in Australia, New Zealand, and the Asia-Pacific region. In the US, GTG brought a legal action for patent infringement against the Applera Corporation and its subsidiaries. In response, Applera counterclaimed that the patents of GTG were invalid because they failed to comply with the requirements of US patent law, such as novelty, inventive step, and written specifications. In New Zealand, the Auckland District Health Board brought legal action in the High Court, seeking a declaration that the patents of GTG were invalid, and that, in any case, the Board has not infringed them. The New Zealand Ministry of Health and the Ministry of Economic Development have reported to Cabinet on the issues relating to the patenting of genetic material. Similarly, the Australian Law Reform Commission (ALRC) has also engaged in an inquiry into gene patents and human health; and the Advisory Council on Intellectual Property (ACIP) has considered whether there should be a new defence in respect of experimental use and research.

'Crossing the line': Criminological expertise, policy advice and the 'quarrelling society'

In October 2009, Professor David Nutt, eminent neuropsychopharmacologist and world leading expert on drugs, was dismissed as Chair of the UK government’s Advisory Council on the Misuse of Drugs for comments he made at the Centre for Crime and Justice Studies’ Eve Saville lecture. This article considers the role of evidence in political decision-making through the case of David Nutt. It is argued that the status of expert knowledge is in crisis for both the natural and the social sciences. We examine the role of the criminological advisor within emerging discourses of public criminology and suggest that high-stakes political issues can open up unprecedented opportunities for critical voices to engage in unbridled critique and to mobilise movements of dissent.

Copyright and creativity: An ongoing debate in the creative industries

This paper critically analyzes the divergent perspectives on how copyright and intellectual property laws impact creativity, innovation, and the creative industries. One perspective defines the creative industries based on copyright as the means by which revenues are generated from innovation and the dissemination of new ideas. At the same time, it has been argued that copyright and intellectual property regimes fetter creativity and innovation, and that this has become even more marked in the context of digital media convergence and the networked global creative economy. These issues have resonated in debates around the creative industries, particularly since the initial DCMS mapping study in the UK in 1998 defined creative industries as combining individual creativity and exploitable forms of intellectual property. The issue of competing claims for the relationship between copyright and the creative industries has also arisen in Australia, with a report by the Australian Law Reform Commission entitled Copyright and the Digital Economy. This paper will consider the competing claims surrounding copyright and the creative industries, and the implications for policy-makers internationally.

Education policy-making and time

This paper examines the global policy convergence toward high-stakes testing in schools and the use of test results to ‘steer at a distance’, particularly as it applies to policy-makers’ promise to improve teacher quality. Using Deleuze’s three syntheses of time in the context of the Australian policy blueprint Quality Education, this paper argues that using test scores to discipline teaching repeats the past habit of policy-making as continuing the problem of the unaccountable teacher. This results in local policy-making enfolding test scores in a pure past where the teacher-as-problem is resolved through the use of data from testing to deliver accountability and transparency. This use of the database returns a digitised form of inspection that is a repetition of the habit of teacher-as-problem. While dystopian possibilities are available through the database, in what Deleuze refers to as a control society, for us the challenge is to consider policy-making as a step into an unknown future, to engage with producing policy that is not grounded on the unconscious interiority of solving the teacher problem, but of imagining new ways of conceiving the relationship between policy-making and teaching.

Performance pay for Australian teachers: A critical policy historiography

In May 2011, the Australian Federal Education Minister announced there would be a unique, innovative and new policy of performance pay for teachers, Rewards for Great Teachers (Garrett, 2011a). In response, this paper uses critical policy historiography to argue that the unintended consequences of performance pay for teachers makes it unlikely it will deliver improved quality or efficiency in Australian schools. What is new, in the Australian context, is that performance pay is one of a raft of education policies being driven by the federal government within a system that constitutionally and historically has placed the responsibility for schooling with the states and territories. Since 2008, a key platform of the Australian federal Labor government has been a commitment to an Education Revolution that would promote quality, equity and accountability in Australian schools. This commitment has resulted in new national initiatives impacting on Australian schools including a high-stakes testing regime 14 National Assessment Program 13 Literacy and Numeracy (NAPLAN) 14a mandated national curriculum (the Australian Curriculum), professional standards for teachers and teacher accreditation 14Australian Institute for Teaching and School Leadership (AITSL) 14and the idea of rewarding excellent teachers through performance pay (Garrett, 2011b). These reforms demonstrate the increased influence of the federal government in education policy processes and the growth of a 1Ccoercive federalism 1D that pits the state and federal governments against each other (Harris-Hart, 2010). Central to these initiatives is the measuring, or auditing, of educational practices and relationships. While this shift in education policy hegemony from state to federal governments has been occurring in Australia at least since the 1970s, it has escalated and been transformed in more recent times with a greater emphasis on national human capital agendas which link education and training to Australia 19s international economic competitiveness (Lingard & Sellar, in press). This paper uses historically informed critical analysis to critique claims about the effects of such policies. We argue that performance pay has a detailed and complex historical trajectory both internationally and within Australian states. Using Gale 19s (2001) critical policy historiography, we illuminate some of the effects that performance pay policies have had on education internationally and in particular within Australia. This critical historical lens also provides opportunities to highlight how teachers have, in the past, tactically engaged with such policies.