Vincent J. Cunningham

Evidence for striatal dopamine release during a video game

Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration,. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.

Parametric imaging of ligand-receptor binding in PET using a simplified reference region model.

A method is presented for the generation of parametric images of radioligand-receptor binding using PET. The method is based on a simplified reference region compartmental model, which requires no arterial blood sampling, and gives parametric images of both the binding potential of the radioligand and its local rate of delivery relative to the reference region. The technique presented for the estimation of parameters in the model employs a set of basis functions which enables the incorporation of parameter bounds. This basis function method (BFM) is compared with conventional nonlinear least squares estimation of parameters (NLM), using both simulated and real data. BFM is shown to be more stable than NLM at the voxel level and is computationally much faster. Application of the technique is illustrated for three radiotracers: [11C]raclopride (a marker of the D2 receptor), [11C]SCH 23390 (a marker of the D1 receptor) in human studies, and [11C]CFT (a marker of the dopamine transporter) in rats. The assumptions implicit in the model and its implementation using BFM are discussed.

Spectral Analysis of Dynamic PET Studies

We describe a new technique for the analysis of dynamic positron emission tomography (PET) studies in humans, where data consist of the time courses of label in tissue regions of interest and in arterial blood, following the administration of radiolabeled tracers. The technique produces a simple spectrum of the kinetic components which relate the tissues response to the blood activity curve. From this summary of the kinetic components, the tissues unit impulse response can be derived. The convolution of the arterial input function with the derived unit impulse response function gives the curve of best fit to the observed tissue data. The analysis makes no a priori assumptions regarding the number of compartments or components required to describe the time course of label in the tissue. Rather, it is based on a general linear model, presented here in a formulation compatible with its solution using standard computer algorithms. Its application is illustrated with reference to cerebral blood flow, glucose utilization, and ligand binding. The interpretation of the spectra, and of the tissue unit impulse response functions, are discussed in terms of vascular components, unidirectional clearance of tracer by the tissue, and reversible and irreversible phenomena. The significance of the number of components which can be identified within a given datum set is also discussed. The technique facilitates the interpretation of dynamic PET data and simplifies comparisons between regions and between subjects.

Positron Emission Tomography Compartmental Models

The current article presents theory for compartmental models used in positron emission tomography (PET). Both plasma input models and reference tissue input models are considered. General theory is derived and the systems are characterized in terms of their impulse response functions. The theory shows that the macro parameters of the system may be determined simply from the coefficients of the impulse response functions. These results are discussed in the context of radioligand binding studies. It is shown that binding potential is simply related to the integral of the impulse response functions for all plasma and reference tissue input models currently used in PET. This article also introduces a general compartmental description for the behavior of the tracer in blood, which then allows for the blood volume-induced bias in reference tissue input models to be assessed.

Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease ☆

In order to establish whether positron emission tomography (PET) can identify metabolic changes in Alzheimers disease at a presymptomatic stage, we have examined 24 asymptomatic at risk individuals from families with Alzheimers disease. A significant reduction in global cerebral metabolic rate for glucose was found when compared with 16 age-matched controls. There was also a focal, parieto-temporal deficit similar to, although less extensive than, that found in 18 symptomatic individuals from familial Alzheimers disease (FAD) pedigrees. Follow up of this cohort will establish whether these metabolic changes relate to a presymptomatic stage of the disease.

KINETICS OF BLOOD‐BRAIN BARRIER TRANSPORT OF PYRUVATE, LACTATE AND GLUCOSE IN SUCKLING, WEANLING AND ADULT RATS

Abstract— The kinetics of the uptake from blood to brain of pyruvate, lactate and glucose have been determined in rats of different ages. The carotid artery single injection technique was used in animals anaesthetized with pentobarbital. The rates of influx for each substrate were determined over a range of concentrations for the different age‐groups. Data were analysed in terms of the Michaelis‐Menten equation with a component to allow for non‐saturable diffusion. Values are given for Km, Vmax and Kd. In suckling rats (15‐21 days) the Vmax values for both pyruvate and lactate were 2.0 μmol g−1 min−1. In 28‐day‐old rats the Vmax values had fallen to one‐half and in adults they were less than one‐tenth. Km, values were higher in the younger animals. The rate of glucose transport in suckling rats was half that of 28‐day‐old and adults although there was no difference with age in the Km values.

Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling.

A kinetic modeling approach for the quantification of in vivo tracer studies with dynamic positron emission tomography (PET) is presented. The approach is based on a general compartmental description of the tracers fate in vivo and determines a parsimonious model consistent with the measured data. The technique involves the determination of a sparse selection of kinetic basis functions from an overcomplete dictionary using the method of basis pursuit denoising. This enables the characterization of the systems impulse response function from which values of the systems macro parameters can be estimated. These parameter estimates can be obtained from a region of interest analysis or as parametric images from a voxel-based analysis. In addition, model order estimates are returned that correspond to the number of compartments in the estimated compartmental model. Validation studies evaluate the methods performance against two preexisting data led techniques, namely, graphical analysis and spectral analysis. Application of this technique to measured PET data is demonstrated using [11C]diprenorphine (opiate receptor) and [11C]WAY-100635 (5-HT1A receptor). Although the method is presented in the context of PET neuroreceptor binding studies, it has general applicability to the quantification of PET/SPECT radiotracer studies in neurology, oncology, and cardiology.

Positron emission tomography Partial volume correction: estimation and algorithms

Partial volume effects in positron emission tomography (PET) lead to quantitative under- and over-estimations of the regional concentrations of radioactivity in reconstructed images and corresponding errors in derived functional or parametric images. The limited resolution of PET leads to “tissue-fraction” effects, reflecting underlying tissue heterogeneity, and “spillover” effects between regions. Addressing the former problem in general requires supplementary data, for example, coregistered high-resolution magnetic resonance images, whereas the latter effect can be corrected for with PET data alone if the point-spread function of the tomograph has been characterized. Analysis of otherwise homogeneous region-of-interest data ideally requires a combination of tissue classification and correction for the point-spread function. The formulation of appropriate algorithms for partial volume correction (PVC) is dependent on both the distribution of the signal and the distribution of the underlying noise. A mathematical framework has therefore been developed to accommodate both of these factors and to facilitate the development of new PVC algorithms based on the description of the problem. Several methodologies and algorithms have been proposed and implemented in the literature in order to address these problems. These methods do not, however, explicitly consider the noise model while differing in their underlying assumptions. The general theory for estimation of regional concentrations, associated error estimation, and inhomogeneity tests are presented in a weighted least squares framework. The analysis has been validated using both simulated and real PET data sets. The relations between the current algorithms and those published previously are formulated and compared. The incorporation of tensors into the formulation of the problem has led to the construction of computationally rapid algorithms taking into account both tissue-fraction and spillover effects. The suitability of their application to dynamic and static images is discussed.

In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography

In vivo opioid receptor binding in the cortical projections of the medial (cingulate and prefrontal cortex) and lateral pain system (primary somatosensory cortex) in male volunteers has been quantitated using [11C]diprenorphine and positron emission tomography. High levels of opioid receptor binding were seen in the cortical projections of the medial pain system in the cingulate and prefrontal cortex as has previously been observed in post-mortem studies. However, a focal reduction of opioid receptor binding was observed and quantitated in the primary motor/sensory strip when compared to surrounding parietal cortex. This new finding suggests that the medial pain system is likely to be more susceptible to exogenous and endogenous opioid neuromodulation than the so-called lateral pain system.

Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited.

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution (VT) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand (VND) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available. We present a transformation of a graphical method, originally introduced by Lassen, using regional estimates of VT alone to determine occupancy, together with an extension that does not require baseline data.