Toward discovery science of human brain function.

Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

The effects of APOE on the functional architecture of the resting brain.

There is a well-established association between APOE genotype and the risk of developing Alzheimer's disease (AD). Relative to individuals with the common ε3/ε3 genotype, carriers of the ε4 allele are at increased risk of developing AD, while carriers of the ε2 allele appear to be protected against the disease. However, we recently reported that in a sample of cognitively healthy adults, both ε4 and ε2 carriers showed nearly identical changes in the pattern of fMRI activity during memory and non-memory tasks, relative to ε3 homozygotes. These findings suggest that the effects of APOE on brain function are not tightly linked to the effects of this gene on AD risk. Here we test the hypothesis that APOE has an intrinsic effect on the brain's functional networks. Resting-state fMRI was used to compare the pattern of functional connectivity of a variety of resting-state networks between 77 cognitively healthy participants aged 32 to 55 with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 8 ε4/ε4). Differences between genotype groups were found in two hippocampal networks, the auditory network, the left frontal-parietal network, and the lateral visual network. While there was considerable variety in the brain regions affected and the direction of change across networks, the main finding was that changes in functional connectivity were similar in ε4 and ε2 carriers, relative to ε3 homozygotes. APOE appears to have an intrinsic effect on the differentiation of functional networks in the brain. This effect is apparent in cognitively healthy adults and does not manifest in a manner reflective of the link between APOE and AD risk. Rather, the effects of APOE on brain function may relate to the role of this gene in neurodevelopment.

Linked independent component analysis for multimodal data fusion.

In recent years, neuroimaging studies have increasingly been acquiring multiple modalities of data and searching for task- or disease-related changes in each modality separately. A major challenge in analysis is to find systematic approaches for fusing these differing data types together to automatically find patterns of related changes across multiple modalities, when they exist. Independent Component Analysis (ICA) is a popular unsupervised learning method that can be used to find the modes of variation in neuroimaging data across a group of subjects. When multimodal data is acquired for the subjects, ICA is typically performed separately on each modality, leading to incompatible decompositions across modalities. Using a modular Bayesian framework, we develop a novel "Linked ICA" model for simultaneously modelling and discovering common features across multiple modalities, which can potentially have completely different units, signal- and contrast-to-noise ratios, voxel counts, spatial smoothnesses and intensity distributions. Furthermore, this general model can be configured to allow tensor ICA or spatially-concatenated ICA decompositions, or a combination of both at the same time. Linked ICA automatically determines the optimal weighting of each modality, and also can detect single-modality structured components when present. This is a fully probabilistic approach, implemented using Variational Bayes. We evaluate the method on simulated multimodal data sets, as well as on a real data set of Alzheimer's patients and age-matched controls that combines two very different types of structural MRI data: morphological data (grey matter density) and diffusion data (fractional anisotropy, mean diffusivity, and tensor mode).

Regional white matter integrity differentiates between vascular dementia and Alzheimer disease.

BACKGROUND AND PURPOSE: Considerable clinical and radiological overlap between vascular dementia (VaD) and Alzheimer disease (AD) often makes the diagnosis difficult. Diffusion-tensor imaging studies showed that fractional anisotropy (FA) could be a useful marker for white matter changes. This study aimed to identify regional FA changes to identify a biomarker that could be used to differentiate VaD from AD. METHODS: T1-weighted and diffusion-tensor imaging scans were obtained in 13 VaD patients, 16 AD patients, and 22 healthy elderly controls. We used tract-based spatial statistics to study regional changes in fractional anisotropy in AD, VaD, and elderly controls. We then used probabilistic tractography to parcel the corpus callosum in 7 regions according to its connectivity with major cerebral cortices using diffusion-tensor imaging data set. We compared the volume and mean FA in each set of transcallosal fibers between groups using ANOVA and then applied a discriminant analysis based on FA and T2-weighted imaging measures. RESULTS: FA reduction in forceps minor was the most significant area of difference between AD and VaD. Segmentation of the corpus callosum using tractography and comparison of FA changes of each segment confirmed the FA changes in transcallosal prefrontal tracts of patients with VaD when compared to AD. The best discriminant model was the combination of transcallosal prefrontal FA and Fazekas score with 87.5% accuracy, 100% specificity, and 93% sensitivity (P<0.0001). CONCLUSIONS: Integrating mean FA in the forceps minor to the Fazekas score provides a useful quantitative marker for differentiating AD from VaD.

The crystal structure of a plant 3-ketoacyl-CoA thiolase reveals the potential for redox control of peroxisomal fatty acid beta-oxidation.

Crystal structures of peroxisomal Arabidopsis thaliana 3-ketoacyl-CoA thiolase (AtKAT), an enzyme of fatty acid beta-oxidation, are reported. The subunit, a typical thiolase, is a combination of two similar alpha/beta domains capped with a loop domain. The comparison of AtKAT with the Saccharomyces cerevisiae homologue (ScKAT) structure reveals a different placement of subunits within the functional dimers and that a polypeptide segment forming an extended loop around the open catalytic pocket of ScKAT converts to alpha-helix in AtKAT, and occludes the active site. A disulfide is formed between Cys192, on this helix, and Cys138, a catalytic residue. Access to Cys138 is determined by the structure of this polypeptide segment. AtKAT represents an oxidized, previously unknown inactive form, whilst ScKAT is the reduced and active enzyme. A high level of sequence conservation is observed, including Cys192, in eukaryotic peroxisomal, but not mitochondrial or prokaryotic KAT sequences, for this labile loop/helix segment. This indicates that KAT activity in peroxisomes is influenced by a disulfide/dithiol change linking fatty acid beta-oxidation with redox regulation.

Placebo response in asthma: a robust and objective phenomenon.

BACKGROUND: Placebos are hypothesized to exert positive effects on medical conditions by enhancing patient expectancies. Recent reviews suggest that placebo benefits are restricted to subjective responses, like pain, but might be ineffective for objective physiologic outcomes. Nevertheless, mind-body links and placebo responsivity in asthma are widely believed to exist. OBJECTIVE: We carried out a randomized, double-blind investigation to (1) determine whether placebo can suppress airway hyperreactivity in asthmatic subjects, (2) quantify the placebo effect, (3) identify predictors of the placebo response, and (4) determine whether physician interventions modify the placebo response. METHODS: In a double-blind, crossover design investigation, 55 subjects with mild intermittent and persistent asthma with stable airway hyperreactivity were randomized to placebo or salmeterol before serial methacholine challenges. Subjects were additionally randomized to physician interactions that communicated either positive or neutral expectancies regarding drug effect. RESULTS: Placebo bronchodilator administration significantly reduced bronchial hyperreactivity compared with baseline (the calculated concentration of methacholine required to induce a 20% decrease in FEV(1) nearly doubled); 18% of subjects were placebo responders by using conservative definitions. Experimental manipulation of physician behavior altered perceptions of the physician but not the magnitude or frequency of the placebo response. CONCLUSIONS: Objective placebo effects exist in asthma. These responses are of significant magnitude and likely to be meaningful clinically. The placebo response was not modulated by alterations in physician behavior in this study. CLINICAL IMPLICATIONS: The placebo response in patients with asthma is important in understanding the limitations of clinical research studies and in maximizing safe and effective therapies. This article confirms the existence of a strong placebo response in an objective and clinically relevant measure of disease activity.

Testing for dual brain processing routes in reading: a direct contrast of chinese character and pinyin reading using FMRI.

Chinese offers a unique tool for testing the effects of word form on language processing during reading. The processes of letter-mediated grapheme-to-phoneme translation and phonemic assembly (assembled phonology) critical for reading and spelling in any alphabetic orthography are largely absent when reading nonalphabetic Chinese characters. In contrast, script-to-sound translation based on the script as a whole (addressed phonology) is absent when reading the Chinese alphabetic sound symbols known as pinyin, for which the script-to-sound translation is based exclusively on assembled phonology. The present study aims to contrast patterns of brain activity associated with the different cognitive mechanisms needed for reading the two scripts. fMRI was used with a block design involving a phonological and lexical task in which subjects were asked to decide whether visually presented, paired Chinese characters or pinyin "sounded like" a word. Results demonstrate that reading Chinese characters and pinyin activate a common brain network including the inferior frontal, middle, and inferior temporal gyri, the inferior and superior parietal lobules, and the extrastriate areas. However, some regions show relatively greater activation for either pinyin or Chinese reading. Reading pinyin led to a greater activation in the inferior parietal cortex bilaterally, the precuneus, and the anterior middle temporal gyrus. In contrast, activation in the left fusiform gyrus, the bilateral cuneus, the posterior middle temporal, the right inferior frontal gyrus, and the bilateral superior frontal gyrus were greater for nonalphabetic Chinese reading. We conclude that both alphabetic and nonalphabetic scripts activate a common brain network for reading. Overall, there are no differences in terms of hemispheric specialization between alphabetic and nonalphabetic scripts. However, differences in language surface form appear to determine relative activation in other regions. Some of these regions (e.g., the inferior parietal cortex for pinyin and fusiform gyrus for Chinese characters) are candidate regions for specialized processes associated with reading via predominantly assembled (pinyin) or addressed (Chinese character) procedures.

HLA-B*35-restricted CD8(+)-T-cell epitope in Mycobacterium tuberculosis Rv2903c.

Few human CD8(+) T-cell epitopes in mycobacterial antigens have been described to date. Here we have identified a novel HLA-B*35-restricted CD8(+) T-cell epitope in Mycobacterium tuberculosis Rv2903c based on a reverse immunogenetics approach. Peptide-specific CD8 T cells were able to kill M. tuberculosis-infected macrophages and produce gamma interferon and tumor necrosis factor alpha.