The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibility, sensitivity and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions which could not previously be answered and, as such, has become an important research area in its own right.In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data . The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL).

Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.

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A fully probabilistic framework is presented for estimating local probability density functions on parameters of interest in a model of diffusion. This technique is applied to the estimation of parameters in the diffusion tensor model, and also to a simple partial volume model of diffusion. In both cases the parameters of interest include parameters defining local fiber direction. A technique is then presented for using these density functions to estimate global connectivity (i.e., the probability of the existence of a connection through the data field, between any two distant points), allowing for the quantification of belief in tractography results. This technique is then applied to the estimation of the cortical connectivity of the human thalamus. The resulting connectivity distributions correspond well with predictions from invasive tracer methods in nonhuman primate. Key words: diffusion-weighted MRI; probability density functions Uncertainty and its representation have an important role to play in any situation where the goal is to infer useful information from noisy data. In diffusion-weighted MRI (DW-MRI) scientists attempt to infer information about, for example, diffusion anisotropy or underlying fiber tract direction, by fitting models of the diffusion and measurement processes to DW-MRI data (e.g., Refs. 1,2). In this scheme there is uncertainty caused both by the noise and artifacts present in any MR scan, but also by the incomplete modeling of the diffusion signal. That is, the true diffusion signal is more complicated than we choose to model. This additional complexity in the diffusion signal appears as residuals when we fit a simple model to the data, causing additional uncertainty in the model parameters. All of the uncertainty in these parameters may be represented in the form of probability density functions (pdfs). This article is essentially divided into two parts, dealing separately with uncertainty at the local and global levels. In the first part, we describe a technique for estimating the pdfs on all parameters in any local model of diffusion. We will show results derived from two simple models of the diffusion process within a voxel: The diffusion tensor model which assumes a local 3D Gaussian diffusion profile, and a simple partial volume model of local diffusion, which assumes that a fraction of diffusion is along a single dominant direction, and that the remainder is isotropic. We will then make suggestions for the extension to more complete models of the diffusion process which are able to account for one, or more, distribution of fiber directions within the voxel. In all of these models, the use of Bayesian techniques allows for the application of prior constraints on parameters in the model where such constraints are sensible. For example, in the fitting of the diffusion tensor model, the eigenvalues of the diffusion tensor are constrained to be positive.The distributions on parameters in a diffusion model are of great significance when making inference on the basis of these param...

Evidence concerning anatomical connectivities in the human brain is sparse and based largely on limited post-mortem observations. Diffusion tensor imaging has previously been used to define large white-matter tracts in the living human brain, but this technique has had limited success in tracing pathways into gray matter. Here we identified specific connections between human thalamus and cortex using a novel probabilistic tractography algorithm with diffusion imaging data. Classification of thalamic gray matter based on cortical connectivity patterns revealed distinct subregions whose locations correspond to nuclei described previously in histological studies. The connections that we found between thalamus and cortex were similar to those reported for non-human primates and were reproducible between individuals. Our results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.

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Reduced fecundity, associated with severe mental disorders1, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism2 schizophrenia3 and mental retardation4. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation4,5 and autism2. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders1–3. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized4. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.