Systemic inflammation enhances stimulant-induced striatal dopamine elevation.

Changes in the mesolimbic dopamine (DA) system are implicated in a range of neuropsychiatric conditions including addiction, depression and schizophrenia. Dysfunction of the neuroimmune system is often comorbid with such conditions and affects similar areas of the brain. The goal of this study was to use positron emission tomography with the dopamine D2 antagonist tracer, 11C-raclopride, to explore the effect of acute immune activation on striatal DA levels. DA transmission was modulated by an oral methylphenidate (MP) challenge in order to reliably elicit DA elevation. Elevation in DA concentration due to MP was estimated via change in 11C-raclopride binding potential from the baseline scan. Prior to the post-MP scan, subjects were pre-treated with either the immune activator lipopolysaccharide (LPS) or placebo (PBO) in a cross-over design. Immune activation was confirmed by measuring tumor necrosis factor alpha (TNFα), interleukin (IL)-6 and IL-8 concentration in plasma. Eight healthy subjects were scanned four times each to determine the MP-induced DA elevation under both LPS and PBO pre-treatment conditions. MP-induced DA elevation in the striatum was significantly greater (P<0.01) after LPS pre-treatment compared to PBO pre-treatment. Seven of eight subjects responded similarly. This effect was observed in the caudate and putamen (P<0.02), but was not present in ventral striatum. DA elevation induced by MP was significantly greater when subjects were pre-treated with LPS compared to PBO. The amplification of stimulant-induced DA signaling in the presence of systemic inflammation may have important implications for our understanding of addiction and other diseases of DA dysfunction.

Selection of weighting factors for quantification of PET radioligand binding using simplified reference tissue models with noisy input functions.

Input function noise contributes to model-predicted values and should be accounted for during parameter estimation. This problem has been examined in the context of PET data analysis using a noisy image-derived arterial input function. Huesman and Mazoyer (1987 Phys. Med. Biol 32 1569-79) incorporated the effect of error in the measured input function into the objective function and observed a subsequent improvement in the accuracy of parameters estimated from a kinetic model of cardiac blood flow. Such a treatment has not been applied to the reference region models commonly used to analyze dynamic positron emission tomography data with receptor-ligand tracers. Here, we propose a strategy for selection of weighting factors that accounts for noise in the reference region input function and test the method on two common formulations of the simplified reference tissue model (SRTM). We present a simulation study which demonstrates that the proposed weighting approach improves the accuracy of estimated binding potential at high noise levels and when the reference tissue and target regions of interest are of comparable size. In the second simulation experiment, we show that using a small, homogeneous reference tissue with our weighting technique may have advantages over input functions derived from a larger (and thus less noisy), heterogeneous region with conventional weighting. A comparative analysis of clinical [(11)C]flumazenil data found a small but significant increase in estimated binding potential when using the proposed weighting method, consistent with the finding of reduced negative bias in our simulation study. The weighting strategy described here accounts for noise in the reference region input function and may improve the performance of the SRTM in applications where data are noisy and the reference region is relatively small. This technique may offer similar benefits to other models using reference region inputs, particularly those derived from the SRTM.

Noninvasive visualization of human dopamine dynamics from PET images.

We recently introduced strategies for extracting temporal patterns of brain dopamine fluctuations from dynamic positron emission tomography (PET) data using the tracer [11C]-raclopride. Each of our methods yields a collection of time-concentration curves for endogenous dopamine. Given a spatially dense collection of curves (i.e., one at every voxel in a region of interest), we produce image volumes of dopamine (DA) concentration, DA(X, t), at multiple voxel locations and each time-frame. The volume over time-frames constitutes a 4D dataset that can be thought of as a DA "movie". There are a number of ways to visualize such data. Viewing cine loops of a slice through the DA volume is one way. Creating images of dopamine peak-time, Tpeak(X), derived from a movie, is another. Each visualization may reveal spatio-temporal patterns of neurotransmitter activity heretofore unobservable. We conducted an initial validation experiment in which identical DA responses were induced by an identical task, initiated at different times by the same subject, in two separate PET scans. A comparison of the resulting Tpeak(X) images revealed a large contiguous cluster of striatal voxels, on each side, whose DA timing was consistent with the relative timing of the tasks. Hence, the DA movies and their respective peak-time images were shown to be new types of functional images that contain bonafide timing information about a neurotransmitter's response to a stimulus.

Estimation from PET data of transient changes in dopamine concentration induced by alcohol: support for a non-parametric signal estimation method.

We previously developed a model-independent technique (non-parametric ntPET) for extracting the transient changes in neurotransmitter concentration from paired (rest & activation) PET studies with a receptor ligand. To provide support for our method, we introduced three hypotheses of validation based on work by Endres and Carson (1998 J. Cereb. Blood Flow Metab. 18 1196-210) and Yoder et al (2004 J. Nucl. Med. 45 903-11), and tested them on experimental data. All three hypotheses describe relationships between the estimated free (synaptic) dopamine curves (FDA(t)) and the change in binding potential (DeltaBP). The veracity of the FDA(t) curves recovered by nonparametric ntPET is supported when the data adhere to the following hypothesized behaviors: (1) DeltaBP should decline with increasing DA peak time, (2) DeltaBP should increase as the strength of the temporal correlation between FDA(t) and the free raclopride (FRAC(t)) curve increases, (3) DeltaBP should decline linearly with the effective weighted availability of the receptor sites. We analyzed regional brain data from 8 healthy subjects who received two [11C]raclopride scans: one at rest, and one during which unanticipated IV alcohol was administered to stimulate dopamine release. For several striatal regions, nonparametric ntPET was applied to recover FDA(t), and binding potential values were determined. Kendall rank-correlation analysis confirmed that the FDA(t) data followed the expected trends for all three validation hypotheses. Our findings lend credence to our model-independent estimates of FDA(t). Application of nonparametric ntPET may yield important insights into how alterations in timing of dopaminergic neurotransmission are involved in the pathologies of addiction and other psychiatric disorders.

Direct reconstruction of kinetic parameter images from dynamic PET data.

Our goal in this paper is the estimation of kinetic model parameters for each voxel corresponding to a dense three-dimensional (3-D) positron emission tomography (PET) image. Typically, the activity images are first reconstructed from PET sinogram frames at each measurement time, and then the kinetic parameters are estimated by fitting a model to the reconstructed time-activity response of each voxel. However, this "indirect" approach to kinetic parameter estimation tends to reduce signal-to-noise ratio (SNR) because of the requirement that the sinogram data be divided into individual time frames. In 1985, Carson and Lange proposed, but did not implement, a method based on the expectation-maximization (EM) algorithm for direct parametric reconstruction. The approach is "direct" because it estimates the optimal kinetic parameters directly from the sinogram data, without an intermediate reconstruction step. However, direct voxel-wise parametric reconstruction remained a challenge due to the unsolved complexities of inversion and spatial regularization. In this paper, we demonstrate and evaluate a new and efficient method for direct voxel-wise reconstruction of kinetic parameter images using all frames of the PET data. The direct parametric image reconstruction is formulated in a Bayesian framework, and uses the parametric iterative coordinate descent (PICD) algorithm to solve the resulting optimization problem. The PICD algorithm is computationally efficient and is implemented with spatial regularization in the domain of the physiologically relevant parameters. Our experimental simulations of a rat head imaged in a working small animal scanner indicate that direct parametric reconstruction can substantially reduce root-mean-squared error (RMSE) in the estimation of kinetic parameters, as compared to indirect methods, without appreciably increasing computation.

Age-related decline in striatal volume in monkeys as measured by magnetic resonance imaging.

Age-related declines in striatal markers for the dopamine system have been demonstrated in several species. The current study investigated structural changes during aging in the rhesus monkey striatum. Male monkeys were studied using a volumetric spoiled gradient recall (SPGR) magnetic resonance imaging protocol. The caudate nucleus and putamen were segmented by manual tracing using landmarks made in the orthogonal planes. The whole brain volume (defined as volume of gray and white matter plus cerebrospinal fluid in ventricles and sulci) was measured using a semi-automated algorithm. There was no correlation between age and whole brain volume. There were age-related declines in normalized (i.e. brain region/whole brain volume) caudate nucleus and putamen volumes. Monkeys in the young group (n = 7, 39-45 months old) had larger volumes of both the caudate nucleus and putamen than animals in the middle-age (n = 5, 120-180 months) or old (n = 7, 291-360 months) groups. The current results provide normative data to assess potential interventions (e.g. caloric restriction) in the aging process.

Loss of D2 receptor binding with age in rhesus monkeys: importance of correction for differences in striatal size.

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

Quantification of dopamine transporter density in monkeys by dynamic PET imaging of multiple injections of 11C-CFT.

Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.

Comparison of two compartmental models for describing receptor ligand kinetics and receptor availability in multiple injection PET studies.

The goal of research with receptor ligands and PET is the characterization of an in vivo system that measures rates of association and dissociation of a ligand-receptor complex and the density of available binding sites. It has been suggested that multiple injection studies of radioactive ligand are more likely to identify model parameters than are single injection studies. Typically, at least one of the late injections is at a low specific activity (SA), so that part of the positron emission tomography (PET) curve reflects ligand dissociation. Low SA injections and the attendant reductions in receptor availability, however, may violate tracer kinetic assumptions, namely, tracer may no longer be in steady state with the total (labeled and unlabeled) ligand. Tissue response becomes critically dependent on the dose of total ligand, and an accurate description of the cold ligand in the tissue is needed to properly model the system. Two alternative models have been applied to the receptor modeling problem, which reduces to describing the time-varying number of available receptor sites. The first (Huang et al., 1989) contains only compartments for the hot ligand, 'hot only' (HO), but indirectly accounts for the action of cold ligand at receptor sites via SA. The second stipulates separate compartments for the hot and cold ligands, 'hot and cold' (HC), thus explicitly calculating available number of receptors. We examined these models and contrasted their abilities to predict PET activity, receptor availability, and SA in each tissue compartment. For multiple injection studies, the models consistently predicted different PET activities--especially following the third injection. Only for very high rate constants were the models identical for multiple injections. In one case, simulated PET curves were quite similar, but discrepancies appeared in predictions of receptor availability. The HO model predicted nonphysiological changes in the availability of receptor sites and introduced errors of 30-60% into estimates of B'max for test data. We, therefore, strongly recommend the use of the HC model for all analyses of multiple injection PET studies.

PET measurement of neuroreceptor occupancy by typical and atypical neuroleptics.

UNLABELLED: The goal of this study was to use PET and 11C-N-methylspiperone (11C-NMSP) to measure the difference in relative occupancy of serotonin (5-hydroxytryptamine-2 or 5-HT2A) and dopamine-2 (D2) neuroreceptors in subjects being treated with typical or atypical antipsychotic drugs. METHODS: We used PET and single-dose 11C-NMSP to measure receptor indices and relative receptor occupancy of 5-HT2A receptors in frontal cortex and D2 receptors in basal ganglia in five subjects who were neuroleptic free, five subjects who were being treated with typical antipsychotic drugs and five subjects who were being treated with clozapine, an atypical antipsychotic drug. RESULTS: Among the three groups, there were significant differences in 5-HT2A indices, D2 indices and the ratio of 5-HT2A to D2 indices. With no overlap, the 5-HT2A index separated all subjects who received clozapine and the D2 index separated the remaining two groups. CONCLUSION: Typical antipsychotic and atypical antipsychotic subjects do have differing patterns of 5-HT2A and D2 relative receptor occupancy when measured with a single PET scan, single 11C-NMSP radiotracer dose and no separately injected "cold" pharmaceutical.

Improved methods for image registration.

We report a system for PET-MRI registration that is improved or optimized in several areas: (1) Automatic scalp/brain segmentation replaces manual drawing operations, (2) a new fast and accurate method of image registration, (3) visual assessment of registration quality is enhanced by composite imaging methods (i.e., fusion) and (4) the entire procedure is embedded in a commercially available scientific visualization package, thereby providing a consistent graphical user interface. The segmentation algorithm was tested on 17 MRI data sets and was successful in all cases. Accuracy of image registration was equal to that of the Woods algorithm, but 10 times faster for PET-PET and 4 times faster for PET-MRI. The image fusion method allows detection of misalignments on the order of 2-3 mm. These results demonstrate an integrated system for intermodality image registration, which is important because the procedure can be performed by technicians with no anatomic knowledge and reduces the required time from hours to about 15 min on a modern computer workstation.

Optimal design of experiments to estimate LDL transport parameters in arterial wall.

To quantify transport processes in atherosclerosis, the arterial wall is often exposed to labeled lipoproteins. In vivo experiments are desirable for estimation of transport parameters, but they are technically difficult. A dynamic mass transfer model has been developed to describe experimental transmural profiles of lipoprotein accumulation as a function of luminal permeability, diffusion, convection, and degradation. To avoid extraneous experiments and to assure successful parameter estimation, an optimal design of experiments is needed. For our purposes a design was considered optimal when it maximized the sensitivity of the model output to changes in parameter values as indicated by the determinant of the Hessian matrix of the objective function. A comparison was made between two designs: dual-time designs prescribing unequal circulation times for two distinguishable injections of labeled low-density lipoprotein (LDL) and dual-species designs requiring simultaneous circulation of LDL and tyramine-cellobiose-modified LDL. Circulation time was optimized for both designs. Although both were heavily dependent on the circulation times, dual-time designs required better preliminary knowledge of parameter values. Because labeled degradation products of the modified tracer become anchored in the arterial tissue, information about the degradation process is retained in the dual-species study. For this reason, dual-species designs were generally superior to dual-time designs.