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Stephen M Smith

Publications and source records attributed to Stephen M Smith.

At least 37 records · Page 2Linked to original sources
PubMed2004

Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus.

Parcellation of the human thalamus based on cortical connectivity information inferred from non-invasive diffusion-weighted images identifies sub-regions that we have proposed correspond to nuclei. Here we test the functional and anatomical validity of this proposal by comparing data from diffusion tractography, cytoarchitecture and functional imaging. We acquired diffusion imaging data in eleven healthy subjects and performed probabilistic tractography from voxels within the thalamus. Cortical connectivity information was used to divide the thalamus into sub-regions with highest probability of connectivity to distinct cortical areas. The relative volumes of these connectivity-defined sub-regions correlate well with volumetric predictions based on a histological atlas. Previously reported centres of functional activation within the thalamus during motor or executive tasks co-localize within atlas regions showing high probabilities of connection to motor or prefrontal cortices, respectively. This work provides a powerful validation of quantitative grey matter segmentation using diffusion tractography in humans. Co-registering thalamic sub-regions from 11 healthy individuals characterizes inter-individual variation in segmentation and results in a population-based atlas of the human thalamus that can be used to assign likely anatomical labels to thalamic locations in standard brain space. This provides a tool for specific localization of functional activations or lesions to putative thalamic nuclei.

Adult↗
PubMed2004

Pre-exposure chemoprophylaxis for HIV: it is time.

The HIV-1 plague continues unabatedly across sub-Saharan Africa. In Botswana and Swaziland, nearly 40% of the entire adult population is already infected. No current program is capable of slowing the advancing tide. An effective vaccine and widespread treatment are years, if not, decades away. In this most urgent situation, I propose that pre-exposure chemoprophylaxis be studied as a means to reduce the spread of HIV-1 among at-risk individuals.

Acquired Immunodeficiency Syndrome↗
PubMed2004

HIV CTL escape: at what cost?

Recent data have established the HIV-1 and SIV escape CTL through epitope mutation. However, three novel studies prove that such escape comes at a "cost" to overall viral fitness. Understanding how HIV-1/SIV escape CTL and the impact of the escape mutations has tremendous importance in developing CTL based vaccines. Further, a CTL based HIV-1 vaccine is likely to have long-term protective effect against disease only if the escape virus is significantly weakened compared with wild type.

AIDS Vaccines↗
PubMed2004

Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition.

BACKGROUND: Choosing between actions associated with uncertain rewards and punishments is mediated by neural circuitry encompassing the orbitofrontal cortex, anterior cingulate cortex (ACC), and striatum; however, the precise conditions under which these different components are activated during decision-making cognition remain uncertain. METHODS: Fourteen healthy volunteers completed an event-based functional magnetic resonance imaging protocol to investigate blood-oxygenation-level-dependent (BOLD) responses during independently modeled phases of choice cognition. In the "decision phase," participants decided which of two simultaneous visually presented gambles they wished to play for monetary reward. The gambles differed in their magnitude of gains, magnitude of losses, and the probabilities with which these outcomes were delivered. In the "outcome phase," the result of each choice was indicated on the visual display. RESULTS: In the decision phase, choices involving large gains were associated with increased BOLD responses in the pregenual ACC, paracingulate, and right posterior orbitolateral cortex compared with choices involving small gains. In the outcome phase, good outcomes were associated with increased BOLD responses in the posterior orbitomedial cortex, subcallosal ACC, and ventral striatum compared with negative outcomes. There was only limited overlap between reward-related activity in ACC and orbitofrontal cortex during the decision and outcome phases. CONCLUSIONS: Neural activity within the medial and lateral orbitofrontal cortex, pregenual ACC, and striatum mediate distinct representations of reward-related information that are deployed at different stages during a decision-making episode.

Adult↗
PubMed2004

Recordings from single neocortical nerve terminals reveal a nonselective cation channel activated by decreases in extracellular calcium.

Synaptic activity causes reductions in cleft [Ca(2+)] that may impact subsequent synaptic efficacy. Using modified patch-clamp techniques to record from single neocortical nerve terminals, we report that physiologically relevant reductions of extracellular [Ca(2+)] ([Ca(2+)](o)) activate voltage-dependent outward currents. These outward currents are carried by a novel nonselective cation (NSC) channel that is indirectly inhibited by various extracellular agents (rank order potency, Gd(3+) > spermidine > Ca(2+) > Mg(2+), typical for [Ca(2+)](o) receptors). The identification of a Ca(2+) sensor-NSC channel pathway establishes the existence of a mechanism by which presynaptic terminals can detect and respond to reductions in cleft [Ca(2+)]. Activation of NSC channels by falls in [Ca(2+)](o) would be expected during periods of high activity in the neocortex and may modulate the excitability of the presynaptic terminal.

Calcium↗
PubMed2004

The evolution of HIV and its consequences.

Since the beginning of the AIDS epidemic in 1981, HIV-1 has demonstrated an amazing ability to mutate. HIV-1 was introduced into the human population in the early to mid twentieth century in central Africa. During ensuing decades, this extraordinary mutational capacity has resulted in the circulation of HIV-1 strains that are quite different from one another, yet still remarkably pathogenic. The potential impact of this viral diversity on treatment, monitoring,and vaccine development is discussed.

AIDS Vaccines↗
PubMed2004

Multilevel linear modelling for FMRI group analysis using Bayesian inference.

Functional magnetic resonance imaging studies often involve the acquisition of data from multiple sessions and/or multiple subjects. A hierarchical approach can be taken to modelling such data with a general linear model (GLM) at each level of the hierarchy introducing different random effects variance components. Inferring on these models is nontrivial with frequentist solutions being unavailable. A solution is to use a Bayesian framework. One important ingredient in this is the choice of prior on the variance components and top-level regression parameters. Due to the typically small numbers of sessions or subjects in neuroimaging, the choice of prior is critical. To alleviate this problem, we introduce to neuroimage modelling the approach of reference priors, which drives the choice of prior such that it is noninformative in an information-theoretic sense. We propose two inference techniques at the top level for multilevel hierarchies (a fast approach and a slower more accurate approach). We also demonstrate that we can infer on the top level of multilevel hierarchies by inferring on the levels of the hierarchy separately and passing summary statistics of a noncentral multivariate t distribution between them.

Bayes Theorem↗
PubMed2004

Constrained linear basis sets for HRF modelling using Variational Bayes.

FMRI modelling requires flexible haemodynamic response function (HRF) modelling, with the HRF being allowed to vary spatially and between subjects. To achieve this flexibility, voxelwise parameterised HRFs have been proposed; however, inference on such models is very slow. An alternative approach is to use basis functions allowing inference to proceed in the more manageable General Linear Model (GLM) framework. However, a large amount of the subspace spanned by the basis functions produces nonsensical HRF shapes. In this work we propose a technique for choosing a basis set, and then the means to constrain the subspace spanned by the basis set to only include sensible HRF shapes. Penny et al. showed how Variational Bayes can be used to infer on the GLM for FMRI. Here we extend the work of Penny et al. to give inference on the GLM with constrained HRF basis functions and with spatial Markov Random Fields on the autoregressive noise parameters. Constraining the subspace spanned by the basis set allows for far superior separation of activating voxels from nonactivating voxels in FMRI data. We use spatial mixture modelling to produce final probabilities of activation and demonstrate increased sensitivity on an FMRI dataset.

Bayes Theorem↗
PubMed2004

Advances in functional and structural MR image analysis and implementation as FSL.

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 that 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).

Bayes Theorem↗
PubMed2004

An alternate conformation and a third metal in PstP/Ppp, the M. tuberculosis PP2C-Family Ser/Thr protein phosphatase.

Serine/threonine protein phosphatases are central mediators of phosphorylation-dependent signals in eukaryotes and a variety of pathogenic bacteria. Here, we report the crystal structure of the intracellular catalytic domain of Mycobacterium tuberculosis PstPpp, a membrane-anchored phosphatase in the PP2C family. Despite sharing the fold and two-metal center of human PP2Calpha, the PstPpp catalytic domain binds a third Mn(2+) in a site created by a large shift in a previously unrecognized flap subdomain adjacent to the active site. Mutations in this site selectively increased the Michaelis constant for Mn(2+) in the reaction of a noncognate, small-molecule substrate, p-nitrophenyl phosphate. The PstP/Ppp structure reveals core functional motifs that advance the framework for understanding the mechanisms of substrate recognition, catalysis, and regulation of PP2C phosphatases.

Amino Acid Sequence↗
PubMed2004

Probabilistic independent component analysis for functional magnetic resonance imaging.

We present an integrated approach to probabilistic independent component analysis (ICA) for functional MRI (FMRI) data that allows for nonsquare mixing in the presence of Gaussian noise. In order to avoid overfitting, we employ objective estimation of the amount of Gaussian noise through Bayesian analysis of the true dimensionality of the data, i.e., the number of activation and non-Gaussian noise sources. This enables us to carry out probabilistic modeling and achieves an asymptotically unique decomposition of the data. It reduces problems of interpretation, as each final independent component is now much more likely to be due to only one physical or physiological process. We also describe other improvements to standard ICA, such as temporal prewhitening and variance normalization of timeseries, the latter being particularly useful in the context of dimensionality reduction when weak activation is present. We discuss the use of prior information about the spatiotemporal nature of the source processes, and an alternative-hypothesis testing approach for inference, using Gaussian mixture models. The performance of our approach is illustrated and evaluated on real and artificial FMRI data, and compared to the spatio-temporal accuracy of results obtained from classical ICA and GLM analyses.

Algorithms↗
PubMed2004

Fully Bayesian spatio-temporal modeling of FMRI data.

We present a fully Bayesian approach to modeling in functional magnetic resonance imaging (FMRI), incorporating spatio-temporal noise modeling and haemodynamic response function (HRF) modeling. A fully Bayesian approach allows for the uncertainties in the noise and signal modeling to be incorporated together to provide full posterior distributions of the HRF parameters. The noise modeling is achieved via a nonseparable space-time vector autoregressive process. Previous FMRI noise models have either been purely temporal, separable or modeling deterministic trends. The specific form of the noise process is determined using model selection techniques. Notably, this results in the need for a spatially nonstationary and temporally stationary spatial component. Within the same full model, we also investigate the variation of the HRF in different areas of the activation, and for different experimental stimuli. We propose a novel HRF model made up of half-cosines, which allows distinct combinations of parameters to represent characteristics of interest. In addition, to adaptively avoid over-fitting we propose the use of automatic relevance determination priors to force certain parameters in the model to zero with high precision if there is no evidence to support them in the data. We apply the model to three datasets and observe matter-type dependence of the spatial and temporal noise, and a negative correlation between activation height and HRF time to main peak (although we suggest that this apparent correlation may be due to a number of different effects).

Bayes Theorem↗
PubMed2003

An in vivo replication-important function in the second coding exon of Tat is constrained against mutation despite cytotoxic T lymphocyte selection.

Human and simian immunodeficiency virus (HIV/SIV) Tat proteins are specified by two coding exons. Tat functions in the transcription of primate lentiviruses. A plethora of in vitro data currently suggests that the second coding exon of Tat is largely devoid of function. However, whether the second exon of Tat contributes functionally to viral pathogenesis in vivo remains unknown. To address this question directly, we compared infection of rhesus macaques with an SIV, engineered to express only the first coding exon of Tat (SIVtat1ex), to counterpart infection with wild-type SIVmac239 virus, which expresses the full 2-exon Tat. This comparison showed that the second coding exon of Tat contributes to chronic SIV replication in vivo. Interestingly, in macaques, we observed a cytotoxic T lymphocytes (CTL) response to the second coding exon of Tat, which appears to durably control SIV replication. When SIV mutated in an attempt to escape this second Tat-exon-CTL, the resulting virus was less replicatively fit and failed to populate the host in vivo. Our study provides the first evidence that the second coding exon in Tat embodies an important function for in vivo replication. We suggest the second coding exon of Tat as an example of a functionally constrained "epitope" whose elicited CTL response cannot be escaped by virus mutation without producing a virus that replicates poorly in vivo.

Amino Acid Sequence↗
PubMed2003

On bias in the estimation of autocorrelations for fMRI voxel time-series analysis.

For fMRI time-series analysis to be statistically valid, it is important to deal correctly with temporal autocorrelation in the noise. Most of the approaches in the literature adopt a two-stage approach in which the autocorrelation structure is estimated using the residuals of an initial model fit. This estimate is then used to "prewhiten" the data and the model before the model is refit to obtain final activation parameter estimates. An assumption implicit in this scheme is that the residuals from the initial model fit represent a realization of the "true" noise process. In general this assumption will not be correct as certain components of the noise will be removed by the model fit. In this paper we examine (i) the form of the bias induced by the initial model fit, (ii) methods of correcting for the bias, and (iii) the impact of bias correction on the model parameter estimates. We find that while bias correction does result in more accurate estimates of the correlation structure, this does not translate into improved estimates of the model parameters. In fact estimates of the model parameters and their standard errors are seen to be so accurate that we conclude that bias correction is unnecessary.

Artifacts↗
PubMed2003

Assessing drought-related ecological risk in the Florida Everglades.

In the winter-spring of 2001, South Florida experienced one of the worst droughts in its recorded history. Out of a myriad of ecological concerns identified during this time, the potential for catastrophic peat fire and negative impacts to wading bird reproduction emerged as critical issues. Water managers attempted to strike a balance between the environment and protection of water supplies for agriculture and urban interests. It became evident, however, that a broad-scale, integrated way to portray and prioritise ecological stress was lacking in the Florida Everglades, despite this being considered a necessary tool for addressing issues of environmental protection. In order to provide a framework for evaluating various water management operations using real-time information, we developed GIS-based indices of peat-fire risk and wading bird habitat suitability. These indices, based on real physical, chemical, and biological data, describe two ecological conditions that help define the physical and biological integrity of the Everglades. In addition to providing continuous, updated assessments throughout the drought period, we incorporated predictive models of water levels to evaluate how various water management alternatives might exacerbate or alleviate ecological stress during this time.

Animals↗