Recovery from acute hypoxia: A systematic review of cognitive and physiological responses during the 'hypoxia hangover'.

Recovery of cognitive and physiological responses following a hypoxic exposure may not be considered in various operational and research settings. Understanding recovery profiles and influential factors can guide post-hypoxia restrictions to reduce the risk of further cognitive and physiological deterioration, and the potential for incidents and accidents. We systematically evaluated the available evidence on recovery of cognitive and basic physiological responses following an acute hypoxic exposure to improve understanding of the performance and safety implications, and to inform post-hypoxia restrictions. This systematic review summarises 30 studies that document the recovery of either a cognitive or physiological index from an acute hypoxic exposure. Titles and abstracts from PubMed (MEDLINE) and Scopus were searched from inception to July 2022, of which 22 full text articles were considered eligible. An additional 8 articles from other sources were identified and also considered eligible. The overall quality of evidence was moderate (average Rosendal score, 58%) and there was a large range of hypoxic exposures. Heart rate, peripheral blood haemoglobin-oxygen saturation and heart rate variability typically normalised within seconds-to-minutes following return to normoxia or hyperoxia. Whereas, cognitive performance, blood pressure, cerebral tissue oxygenation, ventilation and electroencephalogram indices could persist for minutes-to-hours following a hypoxic exposure, and one study suggested regional cerebral tissue oxygenation requires up to 24 hours to recover. Full recovery of most cognitive and physiological indices, however, appear much sooner and typically within ~2-4 hours. Based on these findings, there is evidence to support a 'hypoxia hangover' and a need to implement restrictions following acute hypoxic exposures. The severity and duration of these restrictions is unclear but should consider the population, subsequent requirement for safety-critical tasks and hypoxic exposure.

Cocoa flavanols protect cognitive function, cerebral oxygenation, and mental fatigue during severe hypoxia.

We tested the hypothesis that ingestion of cocoa flavanols would improve cognition during acute hypoxia equivalent to 5,500 m altitude (partial pressure of end-tidal oxygen = 45 mmHg). Using placebo-controlled double-blind trials, 12 participants ingested 15 mg·kg-1 of cocoa flavanols 90 min before completing cognitive tasks during normoxia and either poikilocapnic or isocapnic hypoxia (partial pressure of end-tidal carbon dioxide uncontrolled or maintained at the baseline value, respectively). Cerebral oxygenation was measured using functional near-infrared spectroscopy. Overall cognition was impaired by poikilocapnic hypoxia (main effect of hypoxia, P = 0.008). Cocoa flavanols improved a measure of overall cognitive performance by 4% compared with placebo (effect of flavanols, P = 0.033) during hypoxia, indicating a change in performance from "low average" to "average." The hypoxia-induced decrease in cerebral oxygenation was two-fold greater with placebo than with cocoa flavanols (effect of flavanols, P = 0.005). Subjective fatigue was increased by 900% with placebo compared with flavanols during poikilocapnic hypoxia (effect of flavanols, P = 0.004). Overall cognition was impaired by isocapnic hypoxia (effect of hypoxia, P = 0.001) but was not improved by cocoa flavanols (mean improvement = 1%; effect of flavanols, P = 0.72). Reaction time was impaired by 8% with flavanols during normoxia and further impaired by 11% during isocapnic hypoxia (effect of flavanols, P = 0.01). Our findings are the first to show that flavanol-mediated improvements in cognition and mood during normoxia persist during severe oxygen deprivation, conferring a neuroprotective effect.NEW & NOTEWORTHY We show for the first time that cocoa flavanols exert a neuroprotective effect during severe hypoxia. Following acute cocoa flavanol ingestion, we observed improvements in cognition, cerebral oxygenation, and subjective fatigue during normoxia and severe poikilocapnic hypoxia. Cocoa flavanols did not improve cognition during severe isocapnic hypoxia, suggesting a possible interaction with carbon dioxide.

The effect of acute normobaric hyperoxia on cognition: A systematic review, meta-analysis and meta-regression.

This systematic review, meta-analysis and meta-regression examined the effect of acute normobaric hyperoxic breathing on cognition in healthy humans. 23 studies were included providing 76 effect estimates (EE). Hyperoxic breathing improved memory accuracy (22 EEs; g = 0.34) and speed (9 EEs; g = 0.59), attention accuracy (7 EEs; g = 0.59) and speed (7 EEs; g = 0.51), reaction speed (8 EEs; g = 0.82), crystallised intelligence (7 EEs; g = 0.73), executive function (6 EEs; g = 0.88) and information processing (10 EEs; g = 0.62). However, the overall quality of evidence was low (average Rosendal score of 47%) and there was a large range of study heterogeneity, with prediction intervals often crossing 0; therefore, reducing the reliability of the magnitude of these favourable effects. Oxygen percentage, 100% compared with 22-99% oxygen, temporal position of administration to task performance, and study quality did not influence the overall weighted mean effects for most cognitive domains. Altogether, despite beneficial results, further high quality research is required prior to recommending hyperoxic breathing to enhance cognition.

Cerebral haemodynamics during simulated driving: Changes in workload are detectable with functional near infrared spectroscopy.

Motor vehicle operation is a complicated task and substantial cognitive resources are required for safe driving. Experimental paradigms examining cognitive workload using driving simulators often introduce secondary tasks, such as mathematical exercises, or utilise simulated in-vehicle information systems. The effects of manipulating the demands of the primary driving task have not been examined in detail using advanced neuroimaging techniques. This study used a manipulation of the simulated driving environment to test the impact of increased driving complexity on brain activity. Fifteen participants drove in two scenarios reflecting common driving environments differing in the amount of vehicular traffic, frequency of intersections, number of buildings, and speed limit restrictions. Functional near infrared spectroscopy was used to quantify changes in cortical activity; fifty-five optodes were placed over the prefrontal and occipital cortices, commonly assessed areas during driving. Compared to baseline, both scenarios increased oxyhaemoglobin in the bilateral prefrontal cortex and cerebral blood volume in the right prefrontal cortex (all p ≤ 0.05). Deoxyhaemoglobin decreased at the bilateral aspects of the prefrontal cortex but overall tended to increase in the medial aspect during both scenarios (both p ≤ 0.05). Cerebral oxygen exchange significantly declined at the lateral aspects of the prefrontal cortex, with a small but significant increase seen in the medial aspect (both p < 0.05). There were no significant differences for oxyhaemoglobin, deoxyhaemoglobin, or cerebral blood volume (all p > 0.05). This study demonstrates that functional near infrared spectroscopy is capable of detecting changes in cortical activity elicited by simulated driving tasks but may be less sensitive to variations in driving workload aggregated over a longer duration.

Preclinical Evaluation of TSPO and MAO-B PET Radiotracers in an LPS Model of Neuroinflammation.

Discovery of novel PET radiotracers targeting neuroinflammation (microglia and astrocytes) is actively pursued. Employing a lipopolysaccharide (LPS) rat model, this longitudinal study evaluated the translocator protein 18-kDa radiotracer [18F]FEPPA (primarily microglia) and monoamine oxidase B radiotracers [11C]L-deprenyl and [11C]SL25.1188 (astrocytes preferred). Increased [18F]FEPPA binding peaked at 1 week in LPS-injected striatum whereas increased lazabemide-sensitive [11C]L-deprenyl binding developed later. No increase in radiotracer uptake was observed for [11C]SL25.1188. The unilateral intrastriatal LPS rat model may serve as a useful tool for benchmarking PET tracers targeted toward distinct phases of neuroinflammatory reactions involving both microglia and astrocytes.

Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT1A) receptor antagonist radiotracers.

BACKGROUND: Serotonin 1A (5-HT1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers. RESULTS: Syntheses of 1-3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT1A receptors. Binding of 1-3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α1-adrenergic receptors (4-6-fold less potent than that for 5-HT1A receptor). Radioligands [11C]1-3 were efficiently prepared by 11C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7-11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [11C]1 and [11C]2. In contrast, significant brain uptake of [11C]3 was observed with an early peak SUV of 4-5. However, [11C]3 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies. CONCLUSION: Despite efficient radiolabeling, results from PET imaging experiments limit the application of [11C]3 for in vivo quantification of 5-HT1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α1-adrenergic receptors.

Evaluation of a novel radiotracer for positron emission tomography imaging of reactive oxygen species in the central nervous system.

INTRODUCTION: Few, if any, radiotracers are available for the in vivo imaging of reactive oxygen species (ROS) in the central nervous system. ROS play a critical role in normal cell processes such as signaling and homeostasis but overproduction of ROS is implicated in several disorders. We describe here the radiosynthesis and initial ex vivo and in vivo evaluation of [11C]hydromethidine ([11C]HM) as a radiotracer to image ROS using positron emission tomography (PET). METHODS: [11C]HM and its deuterated isotopologue [11C](4) were produced using [11C]methyl triflate in a one-pot, two-step reaction and purified by high performance liquid chromatography. Ex vivo biodistribution studies were performed after tail vein injections of both radiotracers. To demonstrate sensitivity of uptake to ROS, [11C]HM was administered to rats treated systemically with lipopolysaccharide (LPS). In addition, ex vivo autoradiography and in vivo PET imaging were performed using [11C]HM on rats which had been microinjected with sodium nitroprusside (SNP) to induce ROS. RESULTS: [11C]HM and [11C](4) radiosyntheses were reliable and produced the radiotracers at high specific activities and radiochemical purities. Both radiotracers demonstrated good brain uptake and fast washout of radioactivity, but [11C](4) washout was faster. Pretreatment with LPS resulted in a significant increase in brain retention of radioactivity. Ex vivo autoradiography and PET imaging of rats unilaterally treated with microinjections of SNP demonstrated increased retention of radioactivity in the treated side of the brain. CONCLUSIONS: [11C]HM has the attributes of a radiotracer for PET imaging of ROS in the brain including good brain penetration and increased retention of radioactivity in animal models of oxidative stress.

Whole-body radiation dosimetry of 11C-carbonyl-URB694: a PET tracer for fatty acid amide hydrolase.

UNLABELLED: (11)C-carbonyl-URB694 ((11)C-CURB) is a novel (11)C-labeled suicide irreversible radiotracer for PET developed as a surrogate measure of activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase. The aim of the study was to investigate the whole-body biodistribution and estimate the radiation dosimetry from (11)C-CURB scans in humans. METHODS: Six healthy volunteers (3 men and 3 women) completed a single whole-body scan (∼120 min, 9 time frames) on a PET/CT scanner after administration of (11)C-CURB (∼350 MBq and ∼2 µg). Time-radioactivity curves were extracted in 11 manually delineated organs and corrected for injected activity, specific organ density, and volume to obtain normalized cumulated activities. OLINDA/EXM 1.1 was used to estimate standard internal dose exposure in each organ. The mean effective dose was calculated using the male and female models for the full sample and female-only sample, respectively. RESULTS: (11)C-CURB was well tolerated in all subjects, with no radiotracer-related adverse event reported. The mean effective dose (±SD) was estimated to be 4.6 ± 0.3 µSv/MBq for all subjects and 5.2 ± 0.3 µSv/MBq for the female sample. Organs with the highest normalized cumulated activities (in h) were the liver (0.117), gallbladder wall (0.046), and small intestine (0.033), and organs with the highest dose exposure (in µGy/MBq) were the gallbladder wall (111 ± 60) > liver (21 ± 7), kidney (14 ± 3), and small intestine (12 ± 2). CONCLUSION: Organ radiation exposure for the irreversible fatty acid amide hydrolase enzyme probe (11)C-CURB is within the same range as other radiotracers labeled with (11)C, thus allowing for safe, serial PET scans in the same individuals.

Whole body biodistribution and radiation dosimetry in humans of a new PET ligand, [(18)F]-FEPPA, to image translocator protein (18 kDa).

PURPOSE: [(18)F]-FEPPA is a translocator protein (18 kDa, TSPO) positron emission tomography (PET) radiotracer. Radiation dosimetry was estimated from the whole body biodistribution, taking into consideration TSPO rs6971 (Ala147Thr) polymorphism. PROCEDURES: [(18)F]-FEPPA whole body PET scans were acquired for six healthy subjects. Time-activity curves were generated from regions of interest of nine organs, from which normalized accumulated activities were calculated and thus internal dose, using OLINDA/EXM 1.1. Genotyping of rs6971, associated with high- and low-affinity [(18)F]-FEPPA binding (high-affinity binder (HAB) and low-affinity binder (LAB)), was performed. RESULTS: Five subjects exhibited the C/C (HAB) allele, and the other carried the minor allele T/T (LAB). The LAB whole body biodistribution showed highest radioactivity accumulation in bladder, whereas in HABs, the spleen received the highest dose. The effective dose of the single LAB (16.3 µSv/MBq) was 23 % less than the mean of the HABs (21.0 ± 2.9 µSv/MBq). When including all subjects, the effective dose was 20.2 ± 3.0 µSv/MBq. CONCLUSIONS: [(18)F]-FEPPA radiation dose is consistent with other (18)F-labeled radioligands and the Ala147Thr genotype agreed with [(18)F]-FEPPA distribution.

Whole-body distribution and radiation dosimetry of 11C-(+)-PHNO, a D2/3 agonist ligand.

UNLABELLED: Using PET, we measured the whole-body distribution of (11)C-(+)-PHNO ((11)C-(+)-4-propyl-9-hydroxynaphthoxazine), a D(2/3) agonist, as a function of time in adult subjects in order to determine the internal radiation dose. METHODS: PET whole-body data were acquired after the injection of (11)C-(+)-PHNO (∼360 MBq) in 6 healthy subjects (3 male and 3 female). The PET acquisition duration was a maximum of 112.5 min, and 9 discrete time frames were obtained. After reconstruction of the emission data, 6 organs were identified in the images as exhibiting uptake above background levels. Regions of interest were delineated on these organs, and time-activity curves were generated. The time-activity curve data were corrected for the injected activity, specific organ density, and volume, from which normalized accumulated activities (previously known as residence times) were calculated. The normalized accumulated activities were then used with the software code OLINDA/EXM 1.1 to calculate the internal doses for the standard adult male and female models. RESULTS: The mean effective dose was estimated to be 4.5 ± 0.3 µSv/MBq when all subjects were included and the male model was applied for the dosimetry calculation, and the mean effective dose was estimated to be 5.2 ± 0.2 µSv/MBq when the females were considered separately and the female model was applied for the calculation. The organ receiving the highest dose was the liver (17.9 ± 3.9 µSv/MBq), followed by the kidneys (14.3 ± 3.6 µSv/MBq) and the urinary bladder wall (13.5 ± 3.7 µSv/MBq). CONCLUSION: The estimated radiation doses for (11)C-(+)-PHNO are similar to those reported for other radiotracers labeled with (11)C. (11)C-(+)-PHNO may be used for multiple PET scans in the same subject and remain within regulatory guidelines.

Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography.

This article describes the kinetic modeling of [(18)F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one-tissue model. Estimates of total distribution volume (V(T)), specific distribution volume (V(S)), and binding potential (BP(ND)) demonstrated very good identifiability (based on coefficient of variation (COV)) for all the regions of interest (ROIs) in the gray matter (COV V(T)<7%, COV V(S)<8%, COV BP(ND)<11%). Reduction of the length of the scan to 2 hours is feasible as V(S) and V(T) showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of V(T) and V(S) was still very good with COV<10%, across high-uptake ROIs. The excellent identifiability of V(T) values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of V(T) as an appropriate and feasible outcome measure for [(18)F]-FEPPA.

Elevated brain monoamine oxidase A binding in the early postpartum period.

CONTEXT: The early postpartum period is a time of high risk for a major depressive episode (or postpartum depression), with a prevalence of 13%. During this time, there is a heightened vulnerability for low mood because postpartum blues is common. Severe postpartum blues can herald the onset of postpartum depression. The neurobiological mechanisms to explain postpartum blues and the high risk for the onset of postpartum depression in the first few weeks after delivery are unclear. Estrogen levels drop 100- to 1000-fold during the first 3 to 4 days postpartum, and changes in estrogen levels have an inverse relationship with monoamine oxidase A (MAO-A) density. However, MAO-A levels have never been measured in the early postpartum period. OBJECTIVE: To determine whether brain MAO-A binding is elevated in the early postpartum period. DESIGN: Case-control study. SETTING: Tertiary care academic psychiatric hospital in Toronto, Ontario, Canada. PARTICIPANTS: Fifteen healthy women who were 4 to 6 days postpartum and 15 healthy women who had not recently been postpartum underwent carbon 11-labeled harmine positron emission tomography scanning. All women were nonsmoking and medication free. MAIN OUTCOME MEASURE: MAO-A total distribution volume, an index of MAO-A density, was measured in prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain. RESULTS: MAO-A total distribution volume was significantly elevated (mean, 43%) throughout all analyzed brain regions during the early postpartum period. CONCLUSIONS: Elevated MAO-A levels in the early postpartum period can be interpreted as a marker of a monoamine-lowering process that contributes to the mood change of postpartum blues. Rather than a purely psychosocial model, we propose a neurobiological model of estrogen decline, followed by elevated MAO-A binding, low mood, and subsequently a period of high risk for major depressive episodes. Our model has important implications for preventing postpartum depression and for developing therapeutic strategies that target or compensate for elevated MAO-A levels during postpartum blues.

Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence.

CONTEXT: Highly significant elevations in regional brain monoamine oxidase A (MAO-A) binding were recently reported during major depressive episodes (MDEs) of major depressive disorder (MDD). The relationship between MAO-A levels and selective serotonin reuptake inhibitor (SSRI) treatment, recovery, and recurrence in MDD is unknown. OBJECTIVES: To determine whether brain MAO-A binding changes after SSRI treatment, whether brain MAO-A binding normalizes in subjects with MDD in recovery, and whether there is a relationship between prefrontal and anterior cingulate cortex MAO-A binding in recovery and subsequent recurrence of MDE. DESIGN: Case-control study. SETTING: Tertiary care psychiatric hospital. PARTICIPANTS: Twenty-eight healthy subjects, 16 subjects with an MDE secondary to MDD, and 18 subjects with MDD in recovery underwent carbon 11-labeled harmine positron emission tomography scans. Subjects with MDE were scanned before and after 6 weeks of SSRI treatment. All were otherwise healthy, nonsmoking, and medication free. Subjects with MDD in recovery were followed up for 6 months after MAO-A binding measurement. MAIN OUTCOME MEASURE: Monoamine oxidase A V(T), an index of MAO-A density, was measured in the prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, dorsal putamen, ventral striatum, thalamus, anterior temporal cortex, midbrain, and hippocampus. RESULTS: Monoamine oxidase A V(T) was significantly elevated in each brain region both during MDE and after SSRI treatment as compared with healthy controls. During recovery, MAO-A V(T) was significantly elevated in each brain region; however, those who went on to recurrence had significantly higher MAO-A V(T) in the prefrontal and anterior cingulate cortex than those who did not. CONCLUSIONS: Elevated MAO-A binding after SSRI treatment indicates persistence of a monoamine-lowering process not present in health. This provides a strong conceptual rationale for continuing SSRI treatment during early remission. Greater MAO-A binding in the prefrontal and anterior cingulate cortex in subjects with MDD in recovery and its association with subsequent recurrence argue that deficient monoamine neuromodulation may persist into recovery and contribute to recurrence.

Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain.

The kinetic modeling of [11C]-(+)-PHNO binding to the dopamine D2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [11C]-(+)-PHNO is the first agonist radioligand for the D2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k3/k4 ratios. Coupling K1/k2 between brain regions (Method C) or fixing K1/k2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k3/k4 as compared with an unconstrained 2CM. The k3/k4 obtained with Method D ranged from 0.12+/-0.03 in cerebellum to 3.93+/-0.77 in GP and were similar to those obtained when coupling K1/k2. Binding potentials (BPs) obtained using the simplified reference tissue model (BP(SRTM)) ranged from 2.08+/-0.34 in caudate to 3.55+/-0.78 in GP and were highly correlated with k3/k4 estimates obtained with Method D (r=0.98). However, BP(SRTM) were 11%+/-5% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP(SRTM). This study demonstrates that [11C]-(+)-PHNO can be used for the quantitative measurement of D2/3 densities and should enable further studies of potential D2/3 dysregulation in several important psychiatric and neurologic illnesses.

Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography.

[11C]-(+)-PHNO (4-propyl-9-hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high-affinity states of the D2 receptors (D2-high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]-(+)-PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]-(+)-PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 +/- 0.85. Pre-treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB-277011) antagonists indicated that [11C]-(+)-PHNO binding in striatum is specific to D2 receptors. Within-subject comparisons showed that [11C]-(+)-PHNO BP in striatum was almost 2.5-fold higher than that measured with [11C]-(-)-NPA ([11C]-(-)-N-propyl-norapomorphine). Comparison of the dose-effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [11C]-(+)-PHNO was more sensitive to the dopamine releasing effect of amphetamine than [11C]raclopride. Amphetamine induced up to 83 +/- 4% inhibition of [11C]-(+)-PHNO BP and only up to 56 +/- 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]-(+)-PHNO and [11C]raclopride bindings in two cats showed that the Bmax obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [11C]-(+)-PHNO in brain, its high signal-to-noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [11C]-(+)-PHNO has highly suitable characteristics for probing the D2-high with PET.

The design and implementation of a motion correction scheme for neurological PET.

A method is described to monitor the motion of the head during neurological positron emission tomography (PET) acquisitions and to correct the data post acquisition for the recorded motion prior to image reconstruction. The technique uses an optical tracking system, Polaris, to accurately monitor the position of the head during the PET acquisition. The PET data are acquired in list mode where the events are written directly to disk during acquisition. The motion tracking information is aligned to the PET data using a sequence of pseudo-random numbers, which are inserted into the time tags in the list mode event stream through the gating input interface on the tomograph. The position of the head is monitored during the transmission acquisition, and it is assumed that there is minimal head motion during this measurement. Each event, prompt and delayed, in the list mode event stream is corrected for motion and transformed into the transmission space. For a given line of response, normalization, including corrections for detector efficiency, geometry and crystal interference and dead time are applied prior to motion correction and rebinning in the sinogram. A series of phantom experiments were performed to confirm the accuracy of the method: (a) a point source located in three discrete axial positions in the tomograph field of view, 0 mm, 10 mm and 20 mm from a reference point, (b) a multi-line source phantom rotated in both discrete and gradual rotations through +/- 5 degrees and +/- 15 degrees, including a vertical and horizontal movement in the plane. For both phantom experiments images were reconstructed for both the fixed and motion corrected data. Measurements for resolution, full width at half maximum (FWHM) and full width at tenth maximum (FWTM), were calculated from these images and a comparison made between the fixedand motion corrected datasets. From the point source measurements, the FWHM at each axial position was 7.1 mm in the horizontal direction, and increasing from 4.7 mm at the 0 mm position, to 4.8 mm, 20 mm offset, in the vertical direction. The results from the multi-line source phantom with +/- 5 degrees rotations showed a maximum degradation in FWHM, when compared with the stationary phantom, of 0.6 mm, in the horizontal direction, and 0.3 mm in the vertical direction. The corresponding values for the larger rotation, +/- 15 degrees, were 0.7 mm and 1.1 mm, respectively. The performance of the method was confirmed with a Hoffman brain phantom moved continuously, and a clinical acquisition using [11C]raclopride (normal volunteer). A visual comparison of both the motion and non-motion corrected images of the Hoffman brain phantom clearly demonstrated the efficacy of the method. A sample time-activity curve extracted from the clinical study showed irregularities prior to motion correction, which were removed after correction. A method has been developed to accurately monitor the motion of the head during a neurological PET acquisition, and correct for this motion prior to image reconstruction. The method has been demonstrated to be accurate and does not add significantly to either the acquisition or the subsequent data processing.

Absolute quantification of myocardial blood flow with H(2)(15)O and 3-dimensional PET: an experimental validation.

UNLABELLED: The purpose of this study was to assess a 3-dimensional (3D)-only PET scanner (ECAT EXACT3D) for its use in the absolute quantification of myocardial blood flow (MBF) using H(2)(15)O. METHODS: Nine large white pigs were scanned with H(2)(15)O and C(15)O before and after partially occluding the circumflex (n = 4) or the left anterior descending (n = 5) coronary artery at rest and during hyperemia induced by intravenous dipyridamole. Radioactive microspheres labeled with either (57)Co or (46)Sc were injected during each of the H(2)(15)O scans, which allowed comparison between microsphere and PET measurements of regional MBF. PET analyses of 3D acquisition data were performed using filtered backprojection reconstruction and region-of-interest definition by factor and cluster analysis techniques and single-compartment model quantification. RESULTS: The Hanning filter applied in image reconstruction resulted in a left atrial blood volume recovery factor of 0.84 +/- 0.06. Differences between repeated measurements of recovery were small (mean, -0.8%; range, -6.6% to 3.6%). In 256 paired measurements of MBF ranging from 0.05 to 4.4 mL. g(- 1). min(-1), microsphere and PET measurements were fairly well correlated. The mean difference between the 2 methods was - 0.11 mL. g(-1). min(-1) and the limits of agreement (+2 SD) were -0.82 and 0.60 mL. g(-1). min(-1) (Bland-Altman plot). CONCLUSION: Dynamic measurements with H(2)(15)O using a 3D-only PET tomograph provide reliable and accurate measurements of absolute regional MBF over a wide flow range. The 3D acquisition technique can reduce the radiation dose to the subject while maintaining adequate counting statistics.