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1.  Perceptual classification in a rapidly-changing environment 
Neuron  2011;71(4):725-736.
SUMMARY
Humans and monkeys can learn to classify perceptual information in a statistically optimal fashion if the functional groupings remain stable over many hundreds of trials, but little is known about categorisation when the environment changes rapidly. Here, we used a combination of computational modelling and functional neuroimaging to understand how humans classify visual stimuli drawn from categories whose mean and variance jumped unpredictably. Models based on optimal learning (Bayesian model) and a cognitive strategy (working memory model) both explained unique variance in choice, reaction time and brain activity. However, the working memory model was the best predictor of performance in volatile environments, whereas statistically optimal performance emerged in periods of relative stability. Bayesian and working memory models predicted decision-related activity in distinct regions of the prefrontal cortex and midbrain. These findings suggest that perceptual category judgments, like value-guided choices, may be guided by multiple controllers.
doi:10.1016/j.neuron.2011.06.022
PMCID: PMC3975575  PMID: 21867887
Decision-making; Categorization; fMRI; Computational modelling
2.  THE TOPOGRAPHIC CONNECTOME 
Current opinion in neurobiology  2013;23(2):207-215.
Central to macro-connectomics and much of systems neuroscience is the idea that we can summarise macroscopic brain connectivity using a network of “nodes” and “edges” – functionally distinct brain regions and the connections between them. This is an approach that allows a deep understanding of brain dynamics and how they relate to brain circuitry. This approach, however, ignores key features of anatomical connections, such as spatial arrangement and topographic mappings. In this article, we suggest an alternative to this paradigm. We propose that connection topographies can inform us about brain networks in ways that are complementary to the concepts of “nodes” and “edges”. We also show that current neuroimaging technology is capable of revealing details of connection topographies in vivo. These advances, we hope, will allow us to explore brain connectivity in novel ways in the immediate future.
doi:10.1016/j.conb.2012.12.004
PMCID: PMC3622846  PMID: 23298689
3.  DNA Microarray Gene Expression Profile of Marginal Zone versus Follicular B cells and Idiotype Positive Marginal Zone B cells Before and After Immunization with Streptococcus pneumoniae 1 
Marginal Zone (MZ) B cells play an important role in the clearance of blood-borne bacterial infections via rapid T-independent IgM responses. We have previously demonstrated that MZ B cells respond rapidly and robustly to bacterial particulates. To determine the MZ-specific genes that are expressed to allow for this response, MZ and Follicular (FO) B cells were sort-purified and analyzed via DNA microarray analysis. We identified 181 genes that were significantly different between the two B cell populations. 99 genes were more highly expressed in MZ B cells while 82 genes were more highly expressed in FO B cells. To further understand the molecular mechanisms by which MZ B cells respond so rapidly to bacterial challenge, idiotype positive and negative MZ B cells were sort-purified before (0 hour) or after (1 hour) i.v. immunization with heat killed Streptococcus pneumoniae, R36A, and analyzed via DNA microarray analysis. We identified genes specifically up regulated or down regulated at 1 hour following immunization in the idiotype positive MZ B cells. These results give insight into the gene expression pattern in resting MZ vs. FO B cells and the specific regulation of gene expression in antigen-specific MZ B cells following interaction with antigen.
PMCID: PMC3966313  PMID: 18453586
MZ B cell; FO B cell; microarray; cytokine; idiotype
4.  Fast transient networks in spontaneous human brain activity 
eLife  2014;3:e01867.
To provide an effective substrate for cognitive processes, functional brain networks should be able to reorganize and coordinate on a sub-second temporal scale. We used magnetoencephalography recordings of spontaneous activity to characterize whole-brain functional connectivity dynamics at high temporal resolution. Using a novel approach that identifies the points in time at which unique patterns of activity recur, we reveal transient (100–200 ms) brain states with spatial topographies similar to those of well-known resting state networks. By assessing temporal changes in the occurrence of these states, we demonstrate that within-network functional connectivity is underpinned by coordinated neuronal dynamics that fluctuate much more rapidly than has previously been shown. We further evaluate cross-network interactions, and show that anticorrelation between the default mode network and parietal regions of the dorsal attention network is consistent with an inability of the system to transition directly between two transient brain states.
DOI: http://dx.doi.org/10.7554/eLife.01867.001
eLife digest
When subjects lie motionless inside scanners without any particular task to perform, their brains show stereotyped patterns of activity across regions known as resting state networks. Each network consists of areas with a common function, such as the ‘motor’ network or the ‘visual’ network. The role of resting state networks is unclear, but these spontaneous activity patterns are altered in disorders including autism, schizophrenia, and Alzheimer’s disease.
One puzzling feature of resting state networks is that they seem to last for relatively long times. However, the majority of studies into resting state networks have used fMRI brain scans, in which changes in the level of oxygen in the blood are used as a proxy for the activity of a given brain region. Since changes in blood oxygen occur relatively slowly, the ability of fMRI to detect rapid changes in activity is limited: it is thus possible that the long-lived nature of resting state networks is an artefact of the use of fMRI.
Now, Baker et al. have used a different type of brain scan known as an MEG scan to show that the activity of resting state networks is shorter lived than previously thought. MEG scanners measure changes in the magnetic fields generated by electrical currents in the brain, which means that they can detect alterations in brain activity much more rapidly than fMRI.
MEG recordings from the brains of nine healthy subjects revealed that individual resting state networks were typically stable for only 100 ms to 200 ms. Moreover, transitions between different networks did not occur randomly; instead, certain networks were much more likely to become active after others. The work of Baker et al. suggests that the resting brain is constantly changing between different patterns of activity, which enables it to respond quickly to any given situation.
DOI: http://dx.doi.org/10.7554/eLife.01867.002
doi:10.7554/eLife.01867
PMCID: PMC3965210  PMID: 24668169
magnetoencephalography; resting state; connectivity; non-stationary; hidden Markov model; microstates; human
5.  European Population Substructure Correlates with Systemic Lupus Erythematosus Endophenotypes in North Americans of European Descent 
Genes and immunity  2009;11(6):515-521.
Previous work has demonstrated that northern and southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. Here, 1855 SLE cases of European descent were genotyped for 4965 single nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished northern from southern European ancestry, PC2 differentiated eastern from western European ancestry, and PC3 delineated Ashkenazi Jewish ancestry. Compared to northern European ancestry, southern European ancestry was associated with autoantibody production (OR=1.40, 95% CI 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.
doi:10.1038/gene.2009.80
PMCID: PMC3951966  PMID: 19847193
Systemic lupus erythematosus; epidemiology; population substructure; genetics
6.  Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes  
Ophthalmology  2012;119(9):1874-1885.
Purpose
To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes.
Design
Sibling correlation study and genome-wide association study (GWAS)
Participants
For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls.
Methods
Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.
Main Outcome Measures
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.
Results
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10−5) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the ARMS2/HTRA1 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10−9] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10−14 for combined discovery and replication analysis).
Conclusions
Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.
doi:10.1016/j.ophtha.2012.03.014
PMCID: PMC3899891  PMID: 22705344
7.  Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus 
Nature genetics  2008;40(9):1062-1064.
The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.
doi:10.1038/ng.202
PMCID: PMC3897246  PMID: 19165919
8.  European Genetic Ancestry is Associated with a Decreased Risk of Lupus Nephritis 
Arthritis and rheumatism  2012;64(10):10.1002/art.34567.
Objective
African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than SLE patients of European descent. We investigated whether European genetic ancestry protects against the development of lupus nephritis and explored genetic and socioeconomic factors that might explain this effect.
Methods
This was a cross-sectional study of 1906 adults with SLE. Participants were genotyped for 126 single nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. We used logistic regression to test the association between European ancestry and renal disease. Analyses adjusted for continental ancestries, socioeconomic status, and candidate genes.
Results
Participants (n=1906) had on average 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among participants, 34% (n=656) had renal disease. A 10% increase in European ancestry was associated with a 15% reduction in the odds of having renal disease after adjustment for disease duration and sex (OR 0.85, 95% CI 0.82-0.87, p=1.9 × 10−30). Adjusting for other genetic ancestries, measures of socioeconomic status, or SNPs in genes most associated with renal disease (IRF5 (rs4728142), BLK (rs2736340), STAT4 (rs3024912), ITGAM (rs9937837) and HLA-DRB1*0301 and DRB1*1501, p<0.05) did not substantively alter this relationship.
Conclusion
European ancestry is protective against the development of renal disease in SLE, an effect independent of other genetic ancestries, common risk alleles, and socioeconomic status.
doi:10.1002/art.34567
PMCID: PMC3865923  PMID: 23023776
9.  Model-based analysis of multi-shell diffusion MR data for tractography: How to get over fitting problems 
In this article, we highlight an issue that arises when using multiple b-values in a model-based analysis of diffusion MR data for tractography. The non-mono-exponential decay, commonly observed in experimental data, is shown to induce over-fitting in the distribution of fibre orientations when not considered in the model. Extra fibre orientations perpendicular to the main orientation arise to compensate for the slower apparent signal decay at higher b-values. We propose a simple extension to the ball and stick model based on a continuous Gamma distribution of diffusivities, which significantly improves the fitting and reduces the over-fitting. Using in-vivo experimental data, we show that this model outperforms a simpler, noise floor model, especially at the interfaces between brain tissues, suggesting that partial volume effects are a major cause of the observed non-mono-exponential decay. This model may be helpful for future data acquisition strategies that may attempt to combine multiple shells to improve estimates of fibre orientations in white matter and near the cortex.
doi:10.1002/mrm.24204
PMCID: PMC3359399  PMID: 22334356
10.  Conceptual metaphorical mapping in chimpanzees (Pan troglodytes) 
eLife  2013;2:e00932.
Conceptual metaphors are linguistic constructions. Such a metaphor is humans’ mental representation of social rank as a pyramidal-like structure. High-ranked individuals are represented in higher positions than low-ranked individuals. We show that conceptual metaphorical mapping between social rank and the representational domain exists in our closest evolutionary relatives, the chimpanzees. Chimpanzee participants were requested to discriminate face identities in a vertical arrangement. We found a modulation of response latencies by the rank of the presented individual and the position on the display: a high-ranked individual presented in the higher and a low-ranked individual in the lower position led to quicker identity discrimination than a high-ranked individual in the lower and a low-ranked individual in the higher position. Such a spatial representation of dominance hierarchy in chimpanzees suggests that a natural tendency to systematically map an abstract dimension exists in the common ancestor of humans and chimpanzees.
DOI: http://dx.doi.org/10.7554/eLife.00932.001
eLife digest
It is thought that the ability to connect an abstract concept to something physical helps us to understand abstract ideas more easily. Examples include the use of conceptual metaphors that draw parallels between something abstract, such as social status, and physical position, even though there is no connection between them: familiar examples include phrases such as ‘top dog’ or ‘upper class’. It has long been assumed that the use of such conceptual metaphors is uniquely human.
Many social animals have hierarchies of dominance within groups, with particular individuals being ranked above or below other individuals. Chimpanzees—our closest relatives in the animal kingdom—are a good example of this, and although their cognitive processes are known to be similar to those of humans in many ways, we do not know if they make use of conceptual metaphors. Moreover, we don’t even know if conceptual metaphors can exist in the absence of language.
When researchers want to investigate how concepts are cognitively linked in the brain, they often use ‘coherent’ or ‘incoherent’ stimuli. A good example of an incoherent stimulus would be the word ‘red’ printed in blue ink. Because our neural representations of the colour blue and the word blue are linked, it is harder for a person to read the word red when it is printed in blue than when it is printed in red (which would be a coherent stimulus).
To test whether chimpanzees use a conceptual metaphor in which social status corresponds to height, Dahl and Adachi showed six chimpanzees photographs of four other chimpanzees who were known to them, and tested whether the relative positions of the photographs affected the ability of the chimpanzees to identify which of the two photographs they had been shown earlier. For example, a photograph of a high-ranked, dominant chimpanzee could be shown above a photograph of a lower-ranked chimpanzee (a coherent stimulus) or below a photograph of a lower-ranked chimpanzee (an incoherent stimulus). The chimpanzees doing the tests had to identify which of the photographs they had been shown earlier by touching the correct photograph on a screen.
Dahl and Adachi found that it took longer for chimpanzees to complete the task when the photograph was in the ‘wrong’ position. This suggests that the neural representations of social status and physical position might be linked in chimpanzees. If the social status and the physical position of the photograph match, the chimpanzee doing the test can quickly identify the photograph that it has been shown earlier. However, if they do not match, the conflict between the neural representations of social status and physical position slows down the response. These findings suggest that conceptual metaphors are not uniquely human and, moreover, that they could have emerged before the development of language.
DOI: http://dx.doi.org/10.7554/eLife.00932.002
doi:10.7554/eLife.00932
PMCID: PMC3798977  PMID: 24151544
chimpanzee; conceptual metaphorical mapping; cross-modal mapping; language; linguistic; hierarchy; Other
11.  Brain Systems for Probabilistic and Dynamic Prediction: Computational Specificity and Integration 
PLoS Biology  2013;11(9):e1001662.
Using computational modelling and neuroimaging, two distinct brain systems are shown to use distinct algorithms to make parallel predictions about the environment. The predictions are then optimally combined to control behavior.
A computational approach to functional specialization suggests that brain systems can be characterized in terms of the types of computations they perform, rather than their sensory or behavioral domains. We contrasted the neural systems associated with two computationally distinct forms of predictive model: a reinforcement-learning model of the environment obtained through experience with discrete events, and continuous dynamic forward modeling. By manipulating the precision with which each type of prediction could be used, we caused participants to shift computational strategies within a single spatial prediction task. Hence (using fMRI) we showed that activity in two brain systems (typically associated with reward learning and motor control) could be dissociated in terms of the forms of computations that were performed there, even when both systems were used to make parallel predictions of the same event. A region in parietal cortex, which was sensitive to the divergence between the predictions of the models and anatomically connected to both computational networks, is proposed to mediate integration of the two predictive modes to produce a single behavioral output.
Author Summary
To interact effectively with the environment, brains must predict future events based on past and current experience. Predictions associated with different behavioural domains of the brain are often associated with different algorithmic forms. For example, whereas the motor system makes dynamic moment-by-moment predictions based on physical world models, the reward system is more typically associated with statistical predictions learned over discrete events. However, in perceptually rich natural environments, behaviour is not neatly segmented into tasks like “reward learning” and “motor control.” Instead, many different types of information are available in parallel. The brain must both select behaviourally relevant information and arbitrate between conflicting predictions. To investigate how the brain balances and integrates different types of predictive information, we set up a task in which humans predicted an object's flight trajectory by using one of two strategies: either a statistical model (based on where objects had often landed in the past) or dynamic calculation of the current flight trajectory. Using fMRI, we show that brain activity switches between different regions of the brain, depending on which predictive strategy was used, even though behavioural output remained the same. Furthermore, we found that brain regions involved in selecting actions took into account the predictions from both competing algorithms, weighting each algorithm optimally in terms of the precision with which it could predict the event of interest. Thus, these distinct brain systems compete to control predictive behaviour.
doi:10.1371/journal.pbio.1001662
PMCID: PMC3782423  PMID: 24086106
12.  Trial-Type Dependent Frames of Reference for Value Comparison 
PLoS Computational Biology  2013;9(9):e1003225.
A central question in cognitive neuroscience regards the means by which options are compared and decisions are resolved during value-guided choice. It is clear that several component processes are needed; these include identifying options, a value-based comparison, and implementation of actions to execute the decision. What is less clear is the temporal precedence and functional organisation of these component processes in the brain. Competing models of decision making have proposed that value comparison may occur in the space of alternative actions, or in the space of abstract goods. We hypothesized that the signals observed might in fact depend upon the framing of the decision. We recorded magnetoencephalographic data from humans performing value-guided choices in which two closely related trial types were interleaved. In the first trial type, each option was revealed separately, potentially causing subjects to estimate each action's value as it was revealed and perform comparison in action-space. In the second trial type, both options were presented simultaneously, potentially leading to comparison in abstract goods-space prior to commitment to a specific action. Distinct activity patterns (in distinct brain regions) on the two trial types demonstrated that the observed frame of reference used for decision making indeed differed, despite the information presented being formally identical, between the two trial types. This provides a potential reconciliation of conflicting accounts of value-guided choice.
Author Summary
There are several competing theories of how the primate brain supports the ability to choose between different opportunities to obtain rewards – such as food, shelter, or more abstract goods (e.g. money). These theories suggest that the comparison of different options is either fundamentally dependent upon regions in prefrontal cortex (in which representations of abstract goods are often found), or upon motoric areas such as pre-motor and motor cortices (in which representations of specific actions are found). Evidence has been provided in support of both theories, derived largely from studies using different behavioural tasks. In this study, we show that a subtle manipulation in the behavioural task can have profound consequences for which brain regions appear to support value comparison. We recorded whole-brain magnetoencephalography data whilst subjects performed a decision task. Value comparison-related 13–30 Hz oscillations were found in ‘goods space’ in ventromedial prefrontal cortex in one trial type, but in ‘action space’ in pre-motor and primary motor cortices in another trial type - despite information presented being identical across trial types. This suggests both decision mechanisms are available in the brain, and that the brain adopts the most appropriate mechanism depending upon the current context.
doi:10.1371/journal.pcbi.1003225
PMCID: PMC3772056  PMID: 24068906
13.  RubiX: Combining Spatial Resolutions for Bayesian Inference of Crossing Fibers in Diffusion MRI 
The trade-off between signal-to-noise ratio (SNR) and spatial specificity governs the choice of spatial resolution in magnetic resonance imaging (MRI); diffusion-weighted (DW) MRI is no exception. Images of lower resolution have higher signal to noise ratio, but also more partial volume artifacts. We present a data-fusion approach for tackling this trade-off by combining DW MRI data acquired both at high and low spatial resolution. We combine all data into a single Bayesian model to estimate the underlying fiber patterns and diffusion parameters. The proposed model, therefore, combines the benefits of each acquisition. We show that fiber crossings at the highest spatial resolution can be inferred more robustly and accurately using such a model compared to a simpler model that operates only on high-resolution data, when both approaches are matched for acquisition time.
doi:10.1109/TMI.2012.2231873
PMCID: PMC3767112  PMID: 23362247
Brain; diffusion-weighted imaging; inverse methods; magnetic resonance imaging (MRI); tractography
14.  Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations 
Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.
doi:10.1038/ejhg.2012.277
PMCID: PMC3746253  PMID: 23249952
systemic lupus erythematosus; genetic-association study; Asian; Caucasian
15.  Segregated encoding of reward-identity and stimulus-reward associations in human orbitofrontal cortex 
A dominant focus in studies of learning and decision-making is the neural coding of scalar reward value. This emphasis ignores the fact that choices are strongly shaped by a rich representation of potential rewards. Here, using fMRI adaptation we demonstrate that responses in the human orbitofrontal cortex (OFC) encode a representation of the specific type of food reward predicted by a visual cue. By controlling for value across rewards, and by linking each reward with two distinct stimuli, we could test for representations of reward-identity that were independent of associative information. Our results show reward-identity representations in a medial-caudal region of OFC, independent of the associated predictive stimulus. This contrasts with a more rostro-lateral OFC region encoding reward-identity representations tied to the predicate stimulus. This demonstration of adaptation in OFC to reward specific representations opens an avenue for investigation of more complex decision mechanisms that are not immediately accessible in standard analyses which focus on correlates of average activity.
doi:10.1523/JNEUROSCI.2532-12.2013
PMCID: PMC3586675  PMID: 23407973
16.  Human and monkey ventral prefrontal fibers use the same organizational principles to reach their targets: tracing versus tractography 
This article is a comparative study of white matter projections from ventral prefrontal cortex (vPFC) between human and macaque brains. We test whether the organizational rules that vPFC connections follow in macaques are preserved in humans. These rules concern the trajectories of some of the white matter projections from vPFC, and how the position of regions in the vPFC dictate the trajectories of their projections in the white matter. In order to address this question, we present a novel approach that combines direct tracer measurements of entire white matter trajectories in macaque monkeys with diffusion MRI tractography of both macaques and humans. The approach allows us to provide explicit validation of diffusion tractography and transfer tractography strategies across species to test the extent to which inferences from macaques can be applied to human neuroanatomy. Apart from one exception, we found a remarkable overlap between the two techniques in the macaque. Furthermore the organizational principles followed by vPFC tracts in macaques are preserved in humans.
doi:10.1523/JNEUROSCI.2457-12.2013
PMCID: PMC3602794  PMID: 23407972
18.  CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B cell signaling and activation 
Nature genetics  2012;44(11):1227-1230.
C-src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of Csk with systemic lupus erythematosus (SLE) and refined its location to an intronic polymorphism rs34933034 (OR 1.32, p = 1.04 × 10−9). The risk allele is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, B cell receptor (BCR)-mediated activation of mature B cells, as well as plasma IgM, are increased. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele compared to non-risk haplotypes due to an expansion of the late transitional cells, a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points of B cells.
doi:10.1038/ng.2439
PMCID: PMC3715052  PMID: 23042117
19.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
doi:10.1038/ng.81
PMCID: PMC3712260  PMID: 18204446
20.  Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus 
Nature genetics  2007;40(1):83-89.
Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established1–3. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B6. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs)7,8 and vascular endothelial cells9, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells10. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell–APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.
doi:10.1038/ng.2007.47
PMCID: PMC3705866  PMID: 18059267
21.  Tools of the trade: psychophysiological interactions and functional connectivity 
Psychophysiological interactions (PPIs) analysis is a method for investigating task-specific changes in the relationship between activity in different brain areas, using functional magnetic resonance imaging (fMRI) data. Specifically, PPI analyses identify voxels in which activity is more related to activity in a seed region of interest (seed ROI) in a given psychological context, such as during attention or in the presence of emotive stimuli. In this tutorial, we aim to give a simple conceptual explanation of how PPI analysis works, in order to assist readers in planning and interpreting their own PPI experiments.
doi:10.1093/scan/nss055
PMCID: PMC3375893  PMID: 22569188
psychophysiological interactions; PPI; functional connectivity; resting state
22.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
23.  Ball and Rackets: Inferring Fibre Fanning from Diffusion-weighted MRI 
Neuroimage  2012;60(2):1412-1425.
A number of methods have been proposed for resolving crossing fibres from diffusion-weighted (DW) MRI. However, other complex fibre geometries have drawn minimal attention. In this study, we focus on fibre orientation dispersion induced by within-voxel fanning. We use a multi- compartment, model-based approach to estimate fibre dispersion. Bingham distributions are employed to represent continuous distributions of fibre orientations, centred around a main orientation, and capturing anisotropic dispersion. We evaluate the accuracy of the model for different simulated fanning geometries, under different acquisition protocols and we illustrate the high SNR and angular resolution needs. We also perform a qualitative comparison between our parametric approach and five popular non-parametric techniques that are based on orientation distribution functions (ODFs). This comparison illustrates how the same underlying geometry can be depicted by different methods. We apply the proposed model on high-quality, post-mortem macaque data and present whole-brain maps of fibre dispersion, as well as exquisite details on the local anatomy of fibre distributions in various white matter regions.
doi:10.1016/j.neuroimage.2012.01.056
PMCID: PMC3304013  PMID: 22270351
Diffusion MRI; white matter; parametric deconvolution; fibre fanning; fibre bending; Bingham distribution; macaque
24.  Differences between chimpanzees and bonobos in neural systems supporting social cognition 
Our two closest living primate relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus), exhibit significant behavioral differences despite belonging to the same genus and sharing a very recent common ancestor. Differences have been reported in multiple aspects of social behavior, including aggression, sex, play and cooperation. However, the neurobiological basis of these differences has only been minimally investigated and remains uncertain. Here, we present the first ever comparison of chimpanzee and bonobo brains using diffusion tensor imaging, supplemented with a voxel-wise analysis of T1-weighted images to specifically compare neural circuitry implicated in social cognition. We find that bonobos have more gray matter in brain regions involved in perceiving distress in both oneself and others, including the right dorsal amygdala and right anterior insula. Bonobos also have a larger pathway linking the amygdala with the ventral anterior cingulate cortex, a pathway implicated in both top–down control of aggressive impulses as well as bottom–up biases against harming others. We suggest that this neural system not only supports increased empathic sensitivity in bonobos, but also behaviors like sex and play that serve to dissipate tension, thereby limiting distress and anxiety to levels conducive with prosocial behavior.
doi:10.1093/scan/nsr017
PMCID: PMC3324566  PMID: 21467047
chimpanzee; bonobo; brain; social cognition
25.  Human Connectomics 
Current Opinion in Neurobiology  2011;22(1):144-153.
Recent advances in non-invasive neuroimaging have enabled the measurement of connections between distant regions in the living human brain, thus opening up a new field of research: Human connectomics. Different imaging modalities allow the mapping of structural connections (axonal fiber tracts) as well as functional connections (correlations in time series), and individual variations in these connections may be related to individual variations in behaviour and cognition. Connectivity analysis has already led to several important advances. Segregated brain regions may be identified by their unique patterns of connectivity, structural and functional connectivity may be compared to elucidate how dynamic interactions arise from the anatomical substrate, and the architecture of large-scale networks connecting sets of brain regions may be analyzed in detail. The combination of structural and functional connectivity has begun to reveal key patterns of human brain organization, such as the existence of distinct modules or sub-networks that become engaged in different cognitive tasks. Collectively, advances in human connectomics open up the possibility of studying how brain connections mediate regional brain function and thence behaviour.
doi:10.1016/j.conb.2011.08.005
PMCID: PMC3294015  PMID: 21908183
Neuroimaging; Network; Neuroanatomy; Connectome; Diffusion Imaging; fMRI; Resting-State

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