Biomedical subjects

Alessandro Gozzi

Publications and source records attributed to Alessandro Gozzi.

7 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

Region-specific effects of nicotine on brain activity: a pharmacological MRI study in the drug-naïve rat.

We have applied pharmacological magnetic resonance imaging (phMRI) methods to map the functional response to nicotine in drug-naïve rats. Nicotine (0.35 mg/kg intravenous (i.v.)) increased relative cerebral blood volume (rCBV) in cortical (including medial prefrontal, cingulate orbitofrontal, insular) and subcortical (including amygdala and dorsomedial hippocampus) structures. The pharmacological specificity of the effect was demonstrated by acute pretreatment with the nicotinic acetylcholine receptor (nAChR) ion-channel-blocking agent mecamylamine, which suppressed the rCBV response to nicotine. Control experiments with norepinephrine, a potent non-brain-penetrant vasopressor, at a dose that mimics the cardiovascular response induced by nicotine were performed to assess the potential confounding effects of peripheral blood pressure changes induced by nicotine. In an attempt to highlight the relative contribution of different nAChR subtypes to the observed activation pattern of nicotine, we also investigated the central phMRI response to an acute challenge with (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (cpdA, at 5, 10, 20, and 30 mg/kg i.v.) and 5-iodo-A-85380 (5IA, 5 mg/kg i.v.). CpdA is a selective agonist at homomeric alpha7 nAChRs, while 5IA features high in vivo affinity for the alpha4beta2* and other less-abundant beta2-containing nicotinic receptors. CpdA did not produce significant rCBV changes at any of the doses tested, whereas 5IA induced a pattern of activation very similar to that induced by nicotine. The lack of phMRI response to cpdA together with the high spatial overlap between the activation profile of nicotine and 5IA, suggest that the acute functional response to nicotine in drug-naïve rats is mediated by beta2-containing nAChR isoforms, presumably belonging to the alpha4beta2* subtype.

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↗

PubMed2004

Selective dopamine D(3) receptor antagonist SB-277011-A potentiates phMRI response to acute amphetamine challenge in the rat brain.

Dopamine (DA) receptors are a major target for drugs employed in the treatment of neuropsychiatric disorders such as schizophrenia and drug dependence. The D(3) subtype of the D(2) DA receptor family presents a particularly focal distribution in limbic brain areas known to be associated with cognitive and emotional functions. This study examined the modulation of brain activation induced by acute administration of amphetamine in the rat by the highly selective DA D(3) receptor antagonist SB-277011-A using relative cerebral blood volume (rCBV) pharmacological MRI (phMRI). The acute administration of D-amphetamine (1 mg/kg i.v.) produced a widespread rCBV response that was strongest in cortical regions. SB-277011-A (20 mg/kg i.p.) itself did not produce significant changes in rCBV, but potentiated the phMRI response to 1 mg/kg i.v. D-amphetamine in a regionally specific manner, involving a number of structures outside the focal distribution of the D(3) receptor. Potentiated regions included the accumbens, dorsal caudate putamen, islands of Calleja, thalamus, cingulate cortex, ventral tegmental area, dorsal Raphe nucleus, and ventral subiculum. The increased response following D(3) receptor antagonism is consistent with this receptor mediating an inhibitory action on brain activity following a dopaminergic stimulus.

Amphetamines↗

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↗