Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone.

Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [(18)F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.

Motion correction of PET brain images through deconvolution: II. Practical implementation and algorithm optimization.

Image quality is significantly degraded even by small amounts of patient motion in very high-resolution PET scanners. When patient motion is known, deconvolution methods can be used to correct the reconstructed image and reduce motion blur. This paper describes the implementation and optimization of an iterative deconvolution method that uses an ordered subset approach to make it practical and clinically viable. We performed ten separate FDG PET scans using the Hoffman brain phantom and simultaneously measured its motion using the Polaris Vicra tracking system (Northern Digital Inc., Ontario, Canada). The feasibility and effectiveness of the technique was studied by performing scans with different motion and deconvolution parameters. Deconvolution resulted in visually better images and significant improvement as quantified by the Universal Quality Index (UQI) and contrast measures. Finally, the technique was applied to human studies to demonstrate marked improvement. Thus, the deconvolution technique presented here appears promising as a valid alternative to existing motion correction methods for PET. It has the potential for deblurring an image from any modality if the causative motion is known and its effect can be represented in a system matrix.

Motion correction of PET brain images through deconvolution: I. Theoretical development and analysis in software simulations.

Image quality is significantly degraded even by small amounts of patient motion in very high-resolution PET scanners. Existing correction methods that use known patient motion obtained from tracking devices either require multi-frame acquisitions, detailed knowledge of the scanner, or specialized reconstruction algorithms. A deconvolution algorithm has been developed that alleviates these drawbacks by using the reconstructed image to estimate the original non-blurred image using maximum likelihood estimation maximization (MLEM) techniques. A high-resolution digital phantom was created by shape-based interpolation of the digital Hoffman brain phantom. Three different sets of 20 movements were applied to the phantom. For each frame of the motion, sinograms with attenuation and three levels of noise were simulated and then reconstructed using filtered backprojection. The average of the 20 frames was considered the motion blurred image, which was restored with the deconvolution algorithm. After correction, contrast increased from a mean of 2.0, 1.8 and 1.4 in the motion blurred images, for the three increasing amounts of movement, to a mean of 2.5, 2.4 and 2.2. Mean error was reduced by an average of 55% with motion correction. In conclusion, deconvolution can be used for correction of motion blur when subject motion is known.

Accelerated penalized weighted least-squares and maximum likelihood algorithms for reconstructing transmission images from PET transmission data.

We present penalized weighted least-squares (PWLS) and penalized maximum-likelihood (PML) methods for reconstructing transmission images from positron emission tomography transmission data. First, we view the problem of minimizing the weighted least-squares (WLS) and maximum likelihood objective functions as a sequence of nonnegative least-squares minimization problems. This viewpoint follows from using certain quadratic functions as surrogate functions for the WLS and maximum likelihood objective functions. Second, we construct surrogate functions for a class of penalty functions that yield closed form expressions for the iterates of the PWLS and PML algorithms. Due to the slow convergence of the PWLS and PML algorithms, accelerated versions of them are developed that are theoretically guaranteed to monotonically decrease their respective objective functions. In experiments using real phantom data, the PML images produced the most accurate attenuation correction factors. On the other hand, the PWLS images produced images with the highest levels of contrast for low-count data.

Analysis of PET neurofunctional mapping studies.

In this work, we present a method for analyzing positron emission tomography (PET) functional mapping experiments. The method is useful for identifying statistically significant differences between two PET data sets. First, uniform-variance Z-images are created and then the statistical uncertainty in region-of-interest values are calculated using a previously published method. The Z-images are calculated from the emission sinograms only--the calculation does not use scanner normalization and attenuation corrections and hence variance from these sources is eliminated, with no decrease in validity. Next, the Z-images are analyzed for activation sites using two separate techniques: a cluster analysis method and a change distribution analysis method. Both of these techniques are shown to be effective for objectively locating significantly activated regions from the Z-images. Two advantages of these methods are that they are objective and efficient; all of the parameters necessary in the calculations can be precomputed and stored since they depend only upon the geometry of the scanner.

Butanol is superior to water for performing positron emission tomography activation studies.

[15(O)]Butanol has been shown to be superior to [15(O)]water for measuring cerebral blood flow with positron emission tomography. This work demonstrates that it is also superior for performing activation studies. Data were collected under three conditions: a visual confrontation animal-naming task, nonsense figure size discrimination, and a nonvisual darkroom control task. Time-activity curves (TAC) were obtained for regions known to be activated by the confrontation naming task to compare absolute uptake and the different kinetics of the two tracers. Also, t statistic maps were calculated from the data of 10 subjects for both tracers and compared for magnitude of change and size of activated regions. Peak uptake in the whole-brain TAC were similar for the two tracers. For all regions and conditions, the washout rate of [15(O)]butanol was 41% greater than that of [15(O)]water. At a threshold of 0, the [15(O)]water and [15(O)]butanol percent difference (nonnormalized) and t statistic (global normalization) images are nearly identical, indicating that the same property is being measured with both tracers. The [15(O)]butanol parametric images displayed at a threshold of /t/ = 5 look similar to the [15(O)]water parametric maps displayed at a threshold of /t/ = 4, which is consistent with the observation that t statistic values in [15(O)]butanol images are generally greater. The t statistic values were equal when the [15(O)]butanol parametric map was created from any subset of 6 subjects and the [15(O)]water parametric map was created from all 10 subjects. Fewer subjects need to be studied with [15(O)]butanol to reach the same statistical power as an [15(O)]water-based study.

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy.

OBJECTIVE: To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. BACKGROUND: We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). METHODS: VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. RESULTS: Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). CONCLUSIONS: Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.

Comparison of 2-dimensional and 3-dimensional cardiac 82Rb PET studies.

UNLABELLED: Most new PET scanners have the capability to collect data in 3-dimensional (3D) (septa removed) mode. This allows many more detected events at the cost of increased random events and scatter. In the case of 82Rb imaging, the injected dose might have to be limited to avoid saturating the scanner. We present a comparison of 2-dimensional (2D) and 3D data collection for 82Rb cardiac studies using the ECAT EXACT scanner. METHODS: Resting 82Rb cardiac studies were collected in 2D and 3D modes for 33 consecutive patients. Four experienced physicians rated the images to determine if the different acquisition methods would lead to different patient care. A separate quantitative analysis was performed on data from multiple scans of a thoracic phantom filled to simulate cardiac and background radioactivity corresponding to 82Rb injections between 37 and 1740 MBQ: RESULTS: The 2D and 3D studies were significantly different, with the image quality being poorer in the 3D studies. The scanner collected data at near its maximal counting rate for either 1480-MBq 2D or 37-MBq 3D acquisitions. Because the data collection was counting rate limited in either mode, and there are more random and scatter events in 3D mode, the 2D acquisitions resulted in more detected true events and a better signal-to-noise ratio. CONCLUSION: Cardiac 82Rb studies should be performed in 2D mode when using the ECAT EXACT scanner.

Performance evaluation of the Pico-Count flow-through detector for use in cerebral blood flow PET studies.

UNLABELLED: This study evaluated the Pico-Count (Bioscan, Inc., Washington, DC) flow-through radioactivity detector, designed for use in PET studies of cerebral blood flow. METHODS: The Pico-Count detects the two 511-keV positron annihilation photons with two bismuth germanate detectors operating in coincidence. The detectors, photomultipliers and preamps are housed within a 12 cm x 9 cm x 22 cm box, which includes 16 mm of lead shielding, to allow placement of the detector within 15 cm of the sampling site. The counting electronics are housed in a remote box, which is connected to a laptop computer for process control. The dwell time per sample and the number of samples to collect are entered through the computer and can vary throughout the study. Approximately 22 cm of arterial tubing (which contains 0.11 ml of blood) is looped between the detectors. Typically, blood is withdrawn with a syringe pump at a rate of 2.75 ml/min, which corresponds to a flow rate in the tubing of 9.2 cm/sec. Dispersion within the arterial catheter is measured by observing the response to an input step function and is well-modeled as a monoexponential. RESULTS: The sensitivity is 270 Hz/(microCi/ml), which corresponds to detecting 6.9% of the positron decays occurring within the detector. The peak counting rate after a 12-mCi injection is approximately 2100 Hz, with the background being less than 0.2%. The dispersion time constant is 1.3 sec, and the delay between radioactivity present at the catheter tip and that measured by the detector is 4.1 sec. The cutoff in the power spectral density of typical human arterial blood time radioactivity curves is far less than the corresponding cutoff for the dispersion function. CONCLUSION: The Pico-Count is an excellent detector for continuously monitoring positron radioactivity in blood. Depending on the application, dispersion correction for the detection apparatus may not be needed.

Nitrogen-13-ammonia and PET to detect allograft coronary artery disease after heart transplantation: comparison with coronary angiography.

UNLABELLED: The diffuse nature of allograft coronary artery disease (CAD) suggests that global myocardial blood flow (MBF) may decrease with time after transplantation; therefore the diagnosis of this disease remains problematic. METHODS: To investigate whether PET detects a fall in allograft MBF over time, PET scans (108) were obtained from 43 heart transplant recipients. Thirty-five patients underwent two serial PET scans 1 yr apart. MBF was measured by PET using 13N-ammonia as a tracer. Coronary angiography was performed parallel with PET imaging and compared with perfusion rates measured by PET scans. RESULTS: MBF measured by PET decreased sequentially with time. The mean MBF was 73 +/- 21, 56 +/- 13, 51 +/- 11 and 51 +/- 27 ml/min/100 g of tissue in patients surviving 3 mo, 1, 2 and 3 yr after transplantation, respectively. Significant MBF decrease occurred within 1 yr after transplantation. Sequential PET studies showed a decrease in MBF in 22 of 35 patients (63%). Mean MBF for the first and second scans was 65 +/- 18 and 54 +/- 16, respectively. MBF decrease was more profound in patients (n = 11) angiographic evidence of CAD. There was a trend towards increased rejection and CMV infection rates in patients with decreased MBF. CONCLUSION: With time, PET detects a decrease in MBF in cardiac allografts. The frequency of MBF decrease detected by PET is concordant with the true incidence of allograft CAD, suggesting that sequential PET is a more sensitive modality for monitoring allograft CAD than angiography.

Estimation of left ventricular mass and infarct size from nitrogen-13-ammonia PET images based on pathological examination of explanted human hearts.

The purpose of this study was to develop a technique to quantify left ventricular mass and infarct size in chronic ischemic heart disease from PET images based on correlation with pathological examination of explanted human hearts. Fourteen hearts from patients with cardiomyopathy who had 13N-ammonia scans prior to orthoptic heart transplantation were studied. Accurate estimation of the relative infarct size was possible in patients with a well-delineated, nearly transmural infarct (r = 0.93, y = 1.1x - 0.7, n = 11). Both absolute and relative infarct mass measurements on PET images correlated well with pathological measurements. We identified a population of patients with patchy interstitial or subendocardial scarring with globally reduced perfusion, for which the infarct size could not be estimated using the criteria derived for the patients with well-delineated infarcts.

Biodistribution and radiation dosimetry of the dopamine transporter ligand.

UNLABELLED: 18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad).

Dosimetry of iodine-123-epidepride: a dopamine D2 receptor ligand.

UNLABELLED: Substituted benzamides have been shown to have very high affinity and specificity for the dopamine D2 receptor. One of these is radiolabeled epidepride, an iodine-substituted benzamide currently under evaluation as a SPECT imaging agent. Detailed estimates of the radiation absorbed dose to 26 organs and the whole body from [123I]epidepride have been calculated. METHODS: The dosimetry calculations use a combination of in vivo uptake and biodistribution data from one rhesus monkey and seven humans to estimate residence times in eight organs. The computer program MIRDOSE2 was used to calculate the dosimetry. RESULTS: Results indicate that 75% of the radioactivity is cleared through the urinary tract while the remaining radioactivity clears through the gallbladder and intestinal tract. The radiation absorbed dose can be minimized by administering a high lipid content meal 1.5 hr postinjection to empty the gallbladder and by giving large volumes of fluids throughout the study to induce increased urinary output. CONCLUSION: By emptying the gallbladder and urinary bladder, the lower large intestine becomes the critical organ, 0.102 mGy/MBq (0.38 rad/mCi) followed by the upper large intestine, 0.092 mGy/MBq (0.34 rad/mCi). The effective dose equivalent is 0.025 mSv/MBq (0.092 rem/mCi).

An apparatus and behavioral training protocol to conduct positron emission tomography (PET) neuroimaging in conscious rhesus monkeys.

Nonhuman primates offer a unique resource in neuroimaging research, providing the opportunity to manipulate appropriate biological and behavioral variables under well-controlled experimental conditions in an animal model that is closely related to humans, both functionally and neuroanatomically. The present report describes the development and standardization of PET neuroimaging protocols in conscious rhesus monkeys and their application to characterize the acute effects of cocaine on cerebral blood flow. Specific attention was devoted to the development of an effective and comfortable head restraint device to be used in the imaging of conscious monkeys. The restraint device was designed to attach to a standard primate chair to facilitate frequent immobilization. Subjects received extensive behavioral training prior to neuroimaging in order to ensure their comfort and minimize potential stress associated with the imaging protocols. Functional changes in cerebral blood flow were characterized in three subjects with the positron-emitting tracer 15O water following acute i.v. administration of cocaine. Regions of interest were defined on MRI scans with a high degree of accuracy. Cocaine caused pronounced increases in cerebral blood flow at 5 min postinjection that diminished markedly within 25 min. The results document the feasibility to conduct PET neuroimaging studies of cerebral blood flow in conscious nonhuman primates. Extension of the methodology to include brain activation during behavioral studies could contribute significantly to the growing discipline of behavioral neuroscience.

Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride.

The regional distribution of striatal and extrastriatal dopamine D2 receptors in human brain was studied in vitro with (S)-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-[125I]iodo-2,3-dimethoxybenzamide, [125I]epidepride, using post mortem brain specimens from six subjects. Scatchard analysis of the saturation equilibrium binding in twenty-three regions of post mortem brain revealed highest levels of binding in the caudate (16.5 pmol/g tissue) and putamen (16.6 pmol/g tissue) with lower levels seen in the globus pallidus (7.0 pmol/g tissue), nucleus accumbens (7.2 pmol/g tissue), hypothalamus (1.8 pmol/g tissue), pituitary (1.3 pmol/g tissue), substantia innominata (1.0 pmol/g tissue), and amygdala (0.87 pmol/g tissue). Of note was the presence of dopamine D2 receptors in the four thalamic nuclei studied, i.e. anterior nucleus (1.0 pmol/g tissue), dorsomedial nucleus (0.96 pmol/g tissue), ventral nuclei (0.72 pmol/g tissue), and pulvinar (0.86 pmol/g tissue), at levels comparable to the amygdala (0.87 pmol/g tissue) and considerably higher than levels seen in anterior cingulate (0.26 pmol/g tissue) or anterior hippocampus (0.36 pmol/g tissue). The frontal cortex had very low levels of dopamine D2 receptors (0.17-0.20 pmol/g tissue) while the inferior and medial temporal cortex had relatively higher levels (0.31-0.46 pmol/g tissue). Inhibition of [125I]epidepride binding by a variety of neurotransmitter ligands to striatal, ventral thalamic and inferior temporal cortical homogenates demonstrated that [125I]epidepride binding was potently inhibited only by dopamine D2 ligands. The present study demonstrates that dopamine D2 receptors are present in basal ganglia, many limbic regions, cortex and in the thalamus. The density of thalamic D2 receptors is comparable to many limbic regions and is considerably higher than in cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Visualization of extrastriatal dopamine D2 receptors in the human brain.

[123I]Epidepride, a potent and selective dopamine D2 radioligand, was administered to a 27 year old normal male volunteer. Single photon tomography revealed that peak striatal uptake occurred at 4 h after injection with a striatal:cerebellar ratio of 7.8 rising to over 100 at 18 h post injection. Uptake above the levels seen in cerebellum was also noted in the thalamus, pituitary, hypothalamus and temporal lobe, particularly medially. Single photon tomography with [123I]epidepride allows visualization of extrastriatal dopamine D2 receptors in man.

Compensatory recruitment of neural resources during overt rehearsal of word lists in Alzheimer's disease.

Functional neuroanatomical correlates subserving maintenance rehearsal relative to a reading control task were investigated with positron emission tomography imaging of cerebral blood flow in 6 healthy older participants and 6 patients with mild Alzheimer's disease (AD). Rehearsal and reading rates and number of unique words rehearsed did not differ significantly for the 2 groups. The right dorsolateral prefrontal cortex was activated in both groups during rehearsal, highlighting this region's role in short-term maintenance of verbal information. A shift in cortical processing resources to more anterior brain regions with increased rehearsal list length was seen, likely reflecting greater demands on frontal cortex as cognitive load grows. Whereas controls showed unilateral right frontal activation during rehearsal, AD patients demonstrated bilateral frontal activation, possibly reflecting compensatory recruitment of neural resources.

High affinity dopamine D2 receptor radioligands. 3. [123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain.

Studies of [123I]epidepride uptake in rhesus monkey brain were performed using single photon tomography. Striatal uptake peaked at 0.85% of administered dose/g at 107 min post-injection, then declined slowly to 0.70% of administered dose/g at 6 h. Striatal:posterior brain ratios rose from 2 at 25 min to 6.8 at 105 min, to 15 at 4 h and to 58 at 6.4 h. [123I]Epidepride was displaced by haloperidol (0.1 and 1 mg/kg) with a half-life of washout of 55 min. Little displacement of [123I]epidepride was observed following administration of 1 or 2 mg/kg d-amphetamine, respectively, indicating [123I]epidepride is not easily displaced by endogenous dopamine. In vitro equilibrium binding studies using rat striatum revealed a KD of 46 pM and Bmax of 33 pmol/g tissue at 37 degrees C, while at 25 degrees C the KD was 25 pM and the Bmax 32 pmol/g tissue. In vitro kinetic analysis of association and dissociation curves revealed a half-life for receptor dissociation at 37 degrees C of 15 min and 79-90 min at 25 degrees C. Allowing for the temperature difference, there is good correspondence between in vivo and in vitro dissociation kinetics at 25 degrees C. Increasing in vitro incubation temperature from 25 to 37 degrees C caused a 6-fold increase in the dissociation rate, suggesting that there is a change in binding kinetics at the dopamine D2 receptor at 37 degrees C compared to in vivo binding. The results of this study indicate that [123I]epidepride is an excellent radioligand for SPECT studies of the dopamine D2 receptor in man.

Signal-to-noise ratio in neuro activation PET studies.

It has become commonplace to compare scanner sensitivity characteristics by comparing noise equivalent count rate curves. However, because a 20-cm diameter uniform phantom is drastically different from a human brain, these curves give misleading information when planning a neuro activation PET experiment. Signal-to-noise ratio (SNR) calculations have been performed using measured data (Siemens 921 scanner) from the three-dimensional (3-D) Hoffman brain phantom for the purpose of determining the optimal injection and scanning protocol for [ (15)O] labeled activation experiments. Region of interest (ROI) values along with the variance due to prompt (trues plus randoms) and random events were determined for various regions and radioactivity concentrations. Calculated attenuation correction was used throughout. Scatter correction was not used when calculating the SNR in activation studies because the number of scattered events is almost identical in each data acquisition and hence cancels. The authors results indicate that randoms correction should not be performed and that rather than being limited by the scanner capabilities, neuro activation experiments are limited by the amount of radioactivity that can be injected and the length of time the patient can stay in the scanner.

Optimization of PET activation studies based on the SNR measured in the 3-D Hoffman brain phantom.

This work investigates the noise properties of O-15 water PET images in an attempt to increase the sensitivity of activation studies. A method for computing the amount of noise within a region of interest (ROI) from the uncertainty in the raw data was implemented for three-dimensional (3-D) positron emission tomography (PET). The method was used to study the signal-to-noise ratio (SNR) of regions-of-interest (ROI's) inside a 3-D Hoffman brain phantom. Saturation occurs at an activity concentration of 2.2 mCi/l which corresponds to a 75-mCi O-15 water injection into a normal person of average weight. This establishes the upper limit for injections for human brain studies using 3-D PET on the Siemens ECAT 921 EXACT scanner. Data from human brain activation studies on four normal volunteers using two-dimensional (2-D) PET were analyzed. The biological variation was found to be 5% in 1-ml ROI's. The variance for a complete activation study was calculated, for a variety of protocols, by combining the Poisson noise propagated from the raw data in the phantom experiments with the biological variation. A protocol that is predicted to maximize the SNR in dual-condition activation experiments while remaining below the radiation safety limit is: ten scans with 45 mCi per injection. The data should not be corrected for random or scatter events since they do not help in the identification of activation sites while they do add noise to the image. Due to the lower noise level of 3-D PET, the threshold for detecting a true change in activity concentration is 10%-20% lower than 2-D PET. Because of this, a 3-D activation experiment using the Siemens 921 scanner requires fewer subjects for equal statistical power.