Oestradiol alters central 5-HT1A receptor binding potential differences related to psychosocial stress but not differences related to 5-HTTLPR genotype in female rhesus monkeys.

Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5-HTTLPR) in the regulatory region of the serotonin (5-HT) transporter (5-HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5-HTTLPR polymorphism. The present study determined the effects of social status and the 5-HTTLPR genotype on 5-HT1A receptor binding potential (5-HT1A BP(ND)) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17ß-oestradiol (E(2)) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p-[(18) F]MPPF was performed to determine the levels of 5-HT1A BP(ND) under a non-E(2) and a 3-week E(2) treatment condition. The short variant (s-variant) 5-HTTLPR genotype produced a significant reduction in 5-HT1A BP(ND) in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5-HT1A BP(ND) within the ACC. Both these effects of 5-HTTLPR were unaffected by E(2). Additionally, E(2) reduced 5-HT1A BP(ND) in the dorsal raphe of all females irrespective of psychosocial stress or 5-HTTLPR genotype. Hippocampal 5-HT1A BP(ND) was attenuated in subordinate females regardless of 5-HTTLPR genotype during the non-E(2) condition, an effect that was normalised with E(2). Similarly, 5-HT1A BP(ND) in the hypothalamus was significantly lower in subordinate females regardless of 5-HTTLPR genotype, an effect reversed with E(2). Taken together, the data indicate that the effect of E(2) on modulation of central 5HT1A BP(ND) may only occur in brain regions that show no 5-HTTLPR genotype-linked control of 5-HT1A binding.

CRH receptor antagonism reverses the effect of social subordination upon central GABAA receptor binding in estradiol-treated ovariectomized female rhesus monkeys.

Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social subordination in socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychosocial stress of subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using (18)F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of social subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.

The relation of developmental changes in brain serotonin transporter (5HTT) and 5HT1A receptor binding to emotional behavior in female rhesus monkeys: effects of social status and 5HTT genotype.

The goal of the present study was to examine how social subordination stress and 5HTT polymorphisms affect the development of brain serotonin (5HT) systems during the pubertal transition in female rhesus monkeys. We also examined associations with developmental changes in emotional reactivity in response to a standardized behavioral test, the Human Intruder (HI). Our findings provide the first longitudinal evidence of developmental increases in 5HT1A receptor and 5HTT binding in the brain of female primates from pre- to peripuberty. The increase in 5HT1A BP(ND) in these socially housed female rhesus monkeys is a robust finding, occurring across all groups, regardless of social status or 5HTT genotype, and occurring in the left and right hemispheres of all prefrontal regions studied, as well as the amygdala, hippocampus, hypothalamus, and raphe nuclei. 5HTT BP(ND) also showed an increase with age in raphe, anterior cingulate cortex, and dorsolateral prefrontal cortex. These changes in brain 5HT systems take place as females establish more adult-like patterns of social behavior, as well as during the HI paradigm. Indeed, the main developmental changes in behavior during the HI (increase in freezing and decrease in submission/appeasement) were related to neurodevelopmental increases in 5HT1A receptors and 5HTT, because the associations between these behaviors and 5HT endpoints emerge at peripuberty. We detected an effect of social status on 5HT1A BP(ND) in the hypothalamus and on 5HTT BP(ND) in the orbitofrontal cortex, with subordinates showing higher BP(ND) than dominants in both cases during the pubertal transition. No main effects of 5HTT genotype were observed for 5HT1A or 5HTT BP(ND). Our findings indicate that adolescence in female rhesus monkeys is a period of central 5HT reorganization, partly influenced by exposure to the social stress of subordination, that likely functions to integrate adrenal and gonadal systems and shape the behavioral response to emotionally challenging social situations.

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.

Self-administration of cocaine and the cocaine analog RTI-113: relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys.

Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid phenyl ester (RTI-113), a long-acting, selective, high-affinity dopamine uptake inhibitor. Additionally, the effects of RTI-113 pretreatment on cocaine self-administration were determined. Monkeys were trained to respond under a second-order schedule for intravenous cocaine administration (0.10 or 0.17 mg/kg/infusion). When responding was stable, cocaine (0.0030-1.0 mg/kg/infusion) and RTI-113 (0.010-0.30 mg/kg/infusion) were substituted for the cocaine training dose. Cocaine and RTI-113 were equipotent for their reinforcing effects. However, cocaine maintained higher response rates in two of the three monkeys tested. When administered as a pretreatment, RTI-113 (0.10-0.30 mg/kg) dose-dependently reduced responding maintained by two doses of cocaine. Drug effects on behavior were related to dopamine transporter (DAT) occupancy in monkey striatum during neuroimaging with positron emission tomography. DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. DAT occupancy did not differ markedly across RTI-113 pretreatment doses and ranged between 72-84%. The results suggest that the pharmacokinetic profile of RTI-113 (i.e., long-acting) may influence its ability to maintain self-administration, and therefore its abuse liability. Additionally, high DAT occupancy is required for RTI-113 to reduce cocaine-maintained responding.

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.

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.

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).

18F-labeled FECNT: a selective radioligand for PET imaging of brain dopamine transporters.

Fluorine-18 labeled 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (FECNT) was synthesized in the development of a dopamine transporter (DAT) imaging ligand for positron emission tomography (PET). The methods of radiolabeling and ligand synthesis of FECNT, and the results of the in vitro characterization and in vivo tissue distribution in rats and in vivo PET imaging in rhesus monkeys of [18F]FECNT are described. Fluorine-18 was introduced into 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (4) by preparation of 1-[18F]fluoro-2-tosyloxyethane (2) followed by alkylation of 2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (3) in 21% radiochemical yield (decay corrected to end of bombardment [EOB]). Competition binding in cells stably expressing the transfected human DAT serotonin transporter (SERT) and norepinephrine transporter (NET) labeled by [3H]WIN 35428, [3H]citalopram, and [3H]nisoxetine, respectively, indicated the following order of DAT affinity: GBR 12909 > CIT >> 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(3-fluoropropyl) nortropane (FPCT) > FECNT. The affinity of FECNT for SERT and NET was 25- and 156-fold lower, respectively, than for DAT. Blocking studies were performed in rats with a series of transporter-specific agents and demonstrated that the brain uptake of [18F]FECNT was selective and specific for DAT-rich regions. PET brain imaging studies in monkeys demonstrated high [18F]FECNT uptake in the caudate and putamen that resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 10.5 at 60 min. [18F]FECNT uptake in the caudate/putamen peaked in less than 75 min and exhibited higher caudate- and putamen-to-cerebellum ratios at transient equilibrium than reported for 11C-WIN 35,428, [11C]CIT/RTI-55, or [18F]beta-CIT-FP. Analysis of monkey arterial plasma samples using high performance liquid chromatography determined that there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In equilibrium displacement experiments with CIT in rhesus monkeys, radioactivity in the putamen was displaced with an average half-time of 10.2 min. These results indicate that [18F]FECNT is a radioligand that is superior to 11C-WIN 35,428, [11C]CIT/RTI-55, [18F]beta-CIT-FP, and [18F]FPCT for mapping brain DAT in humans using PET.

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

A confrontational naming task produces congruent increases and decreases in PET and fMRI.

This work uses the well-established (by PET) confrontation naming task to compare PET and fMRI in a cognitive activation experiment. The signal changes from this task are much less than the changes caused by visual or motor activation tasks used in previous comparisons. ANOVA methods adjusted for multiple comparisons were used to determine significant changes in signal between confrontation naming and figure size discrimination tasks. All 17 significantly increased regions (confrontation naming signal greater) seen on one modality were increased on both modalities. Ten of 13 regions that were significantly decreased on one modality were decreased on the other. Three mismatched regions showed a significant decrease on one modality and a nonsignificant increase on the other. This study could not detect a consistent difference in activation site location between PET and fMRI.

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.

Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors.

UNLABELLED: We have developed a new tumor-avid amino acid, 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), labeled with 18F for nuclear medicine imaging. METHODS: [18F]FACBC was prepared with high specific activity (no carrier added [NCA]) and was evaluated for its potential in tumor localization. A comparative study was performed for [18F]FACBC and [18F]2-fluorodeoxyglucose (FDG) in which the uptake of each agent in 9L gliosarcoma (implanted intracerebrally in Fisher 344 rats) was measured. In addition, the first human PET study of [18F]FACBC was performed on a patient with residual glioblastoma multiforme. Quantitative brain images of the patient were obtained by using a Siemens 921 47-slice PET imaging system. RESULTS: In the rat brain, the initial level of radioactivity accumulation after injection of [18F]FACBC was low (0.11 percentage injected dose per gram [%ID/g]) at 5 min and increased slightly to 0.26 %ID/g at 60 min. The tumor uptake exhibited a maximum at 60 min (1.72 %ID/g), resulting in a tumor-to-brain ratio increase of 5.58 at 5 min to 6.61 at 60 min. In the patient, the uptake of [18F]FACBC in the tumor exhibited a maximum concentration of 146 nCi/mL at 35 min after injection. The uptake of radioactivity in the normal brain tissue was low, 21 nCi/mL at 15 min after injection, and gradually increased to 29 nCi/mL at 60 min after injection. The ratio of tumor to normal tissue was 6 at 20 min after injection. The [18F]FACBC PET scan showed intense uptake in the left frontal region of the brain. CONCLUSION: The amino acid FACBC can be radiofluorinated for clinical use. [18F]FACBC is a potential PET tracer for tumor imaging.

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.

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.