Biomedical subjects

Adam J Schwarz

Publications and source records attributed to Adam J Schwarz.

6 recordsLinked to original sources

PubMed2006

In vivo mapping of functional connectivity in neurotransmitter systems using pharmacological MRI.

Pharmacological MRI (phMRI) methods map the hemodynamic response to drug challenge as a surrogate for changes in neuronal activity. However, the central effects of drugs can be complex and include activity at the primary site of action, downstream effects in other brain regions and direct effects on vasculature and neurovascular coupling. Univariate analysis, normally applied to phMRI data, does not discriminate between these effects, and can result in anatomically non-specific activation patterns. We analysed inter-subject correlations in the amplitude of the slow phMRI response to map functionally connected brain regions recruited in response to pharmacological challenge. Application of D-amphetamine and fluoxetine revealed well-defined functional structure underlying the widespread signal changes detected via standard methods. Correlated responses were found to delineate key neurotransmitter pathways selectively targeted by these drugs, corroborating a tight correspondence between the phMRI response and changes in neurotransmitter systems specific to the pharmacological action. In vivo mapping of correlated responses in this way greatly extends the range of information available from phMRI studies and provides a new window into the function of neurotransmitter systems in the active state. This approach may provide new important insights regarding the central systems underlying pharmacological action.

Animals↗

PubMed2006

Study-level wavelet cluster analysis and data-driven signal models in pharmacological MRI.

In pharmacological MRI (phMRI) studies tracking signal changes following the acute administration of a compound, the spatiotemporal pattern of response is often unknown a priori. Moreover, when analysed within a general linear model (GLM) framework, the experimental paradigm of a single injection point under-informs the construction of an appropriate signal model, and information from pharmacokinetics or ancillary in vivo studies may be unavailable or insufficient to accurately describe the dynamic signal changes observed following injection of the drug. Here, we extend the application of a data-driven clustering algorithm, wavelet cluster analysis (WCA), to phMRI data from one or more groups of subjects in a study. A WCA decomposition of spatially concatenated time series' provides a compact overview of spatiotemporal response patterns across cohorts, highlighting typical temporal signatures, brain regions implicated in the response and inter-subject variability. Further, we demonstrate the use of regressors based on selected temporal components as suitable signal models in GLM-based analyses, resulting in a close fit to dynamic phMRI signal changes. This approach is illustrated with simulated data and two representative in vivo phMRI studies in the rat (nicotine and apomorphine challenges).

Animals↗

PubMed2006

A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: application to pharmacological MRI.

We describe a stereotaxic rat brain MRI template set with a co-registered digital anatomical atlas and illustrate its application to the analysis of a pharmacological MRI (phMRI) study of apomorphine. The template set includes anatomical images and tissue class probability maps for brain parenchyma and cerebrospinal fluid (CSF). These facilitate the use of standard fMRI software for spatial normalisation and tissue segmentation of rat brain data. A volumetric reconstruction of the Paxinos and Watson rat brain atlas is also co-localised with the template, enabling the atlas structure and stereotaxic coordinates corresponding to a feature within a statistical map to be interactively reported, facilitating the localisation of functional effects. Moreover, voxels falling within selected brain structures can be combined to define anatomically based 3D volumes of interest (VOIs), free of operator bias. As many atlas structures are small relative to the typical resolution of phMRI studies, a mechanism for defining composite structures as agglomerations of individual atlas structures is also described. This provides a simple and robust means of interrogating structures that are otherwise difficult to delineate and an objective framework for comparing and classifying compounds based on an anatomical profile of their activity. These developments allow a closer alignment of pre-clinical and clinical analysis techniques.

Animals↗

PubMed2005

Functional magnetic resonance mapping of intracerebroventricular infusion of a neuroactive peptide in the anaesthetised rat.

Pharmacological magnetic resonance imaging (phMRI) methods map the cerebral haemodynamic response to challenge with psychotropic agents as a surrogate for drug-induced changes in brain activity. However, many neuroactive compounds present low blood-brain barrier penetration and thus systemic administration may result in insufficient brain concentration. Intracerebroventricular (ICV) administration has been long used as an effective way of bypassing the blood-brain barrier in studies with non-brain-penetrant compounds, such as neuropeptides. In order to extend the range of pharmacological substances accessible to phMRI, we have developed methods to map relative cerebral blood volume (rCBV) changes induced by in situ ICV administration of neuroactive agents in the anaesthetised rat. We have applied this method to study for the first time the phMRI response to central administration of a neuropeptide, the metabolically stable and potent NK1 receptor agonist GR-73632. ICV administration of 4.2 pmol of GR-73632 produced a rapid onset and sustained rCBV increase in several brain structures, such as the amygdala, the caudate putamen and the cortex. These results demonstrate the feasibility of phMRI as a tool to study the functional correlates of brain activity induced by central administration of neuroactive agents.

Anesthetics↗

PubMed2005

Wavelet-based cluster analysis: data-driven grouping of voxel time courses with application to perfusion-weighted and pharmacological MRI of the rat brain.

MRI time series experiments produce a wealth of information contained in two or three spatial dimensions that evolve over time. Such experiments can, for example, localize brain response to pharmacological stimuli, but frequently the spatiotemporal characteristics of the cerebral response are unknown a priori and variable, and thus difficult to evaluate using hypothesis-based methods alone. Here we used features in the temporal dimension to group voxels with similar time courses based on a nonparametric discrete wavelet transform (DWT) representation of each time course. Applying the DWT to each voxel decomposes its temporal information into coefficients associated with both time and scale. Discarding scales in the DWT that are associated with high-frequency oscillations (noise) provided a straight-forward data reduction step and decreased the computational burden. Optimization-based clustering was then applied to the remaining wavelet coefficients in order to produce a finite number of voxel clusters. This wavelet-based cluster analysis (WCA) was evaluated using two representative classes of MRI neuroimaging experiments. In perfusion-weighted MRI, following occlusion of the middle cerebral artery (MCAO), WCA differentiated healthy tissue and different regions within the ischemic hemisphere. Following an acute cocaine challenge, WCA localized subtle differences in the pharmacokinetic profile of the cerebral response. We conclude that WCA provides a robust method for blind analysis of time series image data.

Animals↗

PubMed2003

Functional MRI using intravascular contrast agents: detrending of the relative cerebrovascular (rCBV) time course.

In pharmacological fMRI experiments in animal models, blood pool contrast agents may be used to map cerebral blood volume change as a surrogate for neural activation. When the background signal drift due to contrast agent washout is non-negligible over the duration of the signal changes of interest, time-course detrending is essential for accurate interpretation of the experiment. Detrending approaches based on estimation of the background signal from a baseline period of the time course prior to pharmacological (or functional) challenge were evaluated with the aim of identifying a robust method of estimating the contrast agent washout contribution to the background signal drift. For fMRI studies in the rat, it was found that a constrained fit of a mono-exponential washout model was more accurate than a constant background approximation and unconstrained fits for experiments investigating the functional response to rapid pharmacological challenges such as cocaine and amphetamine. Moreover, the constrained fitting approach allows shorter baseline periods than unconstrained extrapolation, reducing the required duration of the experiment.

Amphetamine↗