Name: radiotracer administration for high temporal resolution positron emission tomography of the human brain: application to fdg-fpet
Uploaded: 2019-10-22T14:00:00
Description: Watch this Scientific Journal Video about Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET at JoVE.com

Jamadar is supported by an Australian Council for Research (ARC) Discovery Early Career Researcher Award (DECRA DE150100406). Jamadar, Ward, and Egan are supported by the ARC Centre of Excellence for Integrative Brain Function (CE114100007). Chen and Li are supported by funding from the Reignwood Cultural Foundation.
Jamadar, Ward, Carey, and McIntyre designed the protocol. Carey, McIntyre, Sasan, and Fallon collected the data. Jamadar, Ward, Parkes, and Sasan analyzed the data. Jamadar, Ward, Carey, and McIntyre wrote the first draft of the manuscript. All authors have reviewed and approved the final version.

This protocol has been reviewed and approved by the Monash University Human Research Ethics Committee (approval number CF16/1108 - 2016000590) in accordance with the Australian National Statement on Ethical Conduct in Human Research24. Procedures were developed under the guidance of an accredited Medical Physicist, Nuclear Medicine Technologist, and clinical radiographer. Researchers should refer to their local experts and guidelines for the administration of ionizing radiation in humans.
<p c...

<ol>
	<li>Heurling, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+positron+emission+tomography+in+brain+research.">Quantitative positron emission tomography in brain research.</a> Brain Research. 1670, 220-234 (2017).</li><li>Chen, Z., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=From+simultaneous+to+synergistic+MR-PET+brain+imaging:+A+review+of+hybrid+MR-PET+imaging+methodologies.">From simultaneous to synergistic MR-PET brain imaging: A review of hybrid MR-PET imaging methodologies.</a> Human Brain Mapping. 39 (12), 5126-5144 (2018).</li><li>Jones, T., Rabiner, E. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+development,+past+achievements,+and+future+directions+of+brain+PET.">The development, past achievements, and future directions of brain PET.</a> Journal of Cerebral Blood Flow &amp; Metabolism. 32 (7), 1426-1454 (2012).</li><li>Kety, S. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Metabolism of the nervous system. , 221-237 (1957).</li><li>Sokoloff, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+metabolism+of+the+central+nervous+system+in+vivo.">The metabolism of the central nervous system in vivo.</a> Handbook of Physiology, section I, neurophysiology. 3, 1843-1864 (1960).</li><li>Harris, J. J., Jolivet, R., Attwell, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synaptic+energy+use+and+supply.">Synaptic energy use and supply.</a> Neuron. 75 (5), 762-777 (2012).</li><li>Mosconi, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=FDG-PET+changes+in+brain+glucose+metabolism+from+normal+cognition+to+pathologically+verified+Alzheimer's+disease.">FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease.</a> European Journal of Nuclear Medicine and Molecular Imaging. 36 (5), 811-822 (2009).</li><li>Pagano, G., Niccolini, F., Politis, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Current+status+of+PET+imaging+in+Huntington's+disease.">Current status of PET imaging in Huntington's disease.</a> European Journal of Nuclear Medicine and Molecular Imaging. 43 (6), 1171-1182 (2016).</li><li>Petit-Taboue, M., Landeau, B., Desson, J., Desgranges, B., Baron, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+healthy+aging+on+the+regional+cerebral+metabolic+rate+of+glucose+assessed+with+statistical+parametric+mapping.">Effects of healthy aging on the regional cerebral metabolic rate of glucose assessed with statistical parametric mapping.</a> Neuroimage. 7 (3), 176-184 (1998).</li><li>Chugani, H. T., Phelps, M. E., Mazziotta, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Positron+emission+tomography+study+of+human+brain+functional+development.">Positron emission tomography study of human brain functional development.</a> Annals of Neurology. 22 (4), 487-497 (1987).</li><li>Phelps, M. E., Mazziotta, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Positron+emission+tomography:+human+brain+function+and+biochemistry.">Positron emission tomography: human brain function and biochemistry.</a> Science. 228 (4701), 799-809 (1985).</li><li>Zimmer, E. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=[18+F]+FDG+PET+signal+is+driven+by+astroglial+glutamate+transport.">[18 F] FDG PET signal is driven by astroglial glutamate transport.</a> Nature Neuroscience. 20 (3), 393 (2017).</li><li>Roberts, R. P., Hach, S., Tippett, L. J., Addis, D. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Simpson's+paradox+and+fMRI:+Similarities+and+differences+between+functional+connectivity+measures+derived+from+within-subject+and+across-subject+correlations.">The Simpson's paradox and fMRI: Similarities and differences between functional connectivity measures derived from within-subject and across-subject correlations.</a> Neuroimage. 135, 1-15 (2016).</li><li>Horwitz, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+elusive+concept+of+brain+connectivity.">The elusive concept of brain connectivity.</a> Neuroimage. 19 (2), 466-470 (2003).</li><li>Moses, W. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fundamental+limits+of+spatial+resolution+in+PET.">Fundamental limits of spatial resolution in PET.</a> Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 648, S236-S240 (2011).</li><li>Tomasi, D. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dynamic+brain+glucose+metabolism+identifies+anti-correlated+cortical-cerebellar+networks+at+rest.">Dynamic brain glucose metabolism identifies anti-correlated cortical-cerebellar networks at rest.</a> Journal of Cerebral Blood Flow &amp; Metabolism. 37 (12), 3659-3670 (2017).</li><li>Hahn, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantification+of+task+specific+glucose+metabolism+with+constant+infusion+of+18F-FDG.">Quantification of task specific glucose metabolism with constant infusion of 18F-FDG.</a> Journal of Nuclear Medicine. 57 (12), 1933-1940 (2016).</li><li>Hahn, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Task-relevant+brain+networks+identified+with+simultaneous+PET/MR+imaging+of+metabolism+and+connectivity.">Task-relevant brain networks identified with simultaneous PET/MR imaging of metabolism and connectivity.</a> Brain Structure and Function. 223 (3), 1369-1378 (2018).</li><li>Jamadar, S. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Simultaneous+task-based+BOLD-fMRI+and+[18-F]+FDG+functional+PET+for+measurement+of+neuronal+metabolism+in+the+human+visual+cortex.">Simultaneous task-based BOLD-fMRI and [18-F] FDG functional PET for measurement of neuronal metabolism in the human visual cortex.</a> Neuroimage. 189, 258-266 (2019).</li><li>Rischka, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reduced+task+durations+in+functional+PET+imaging+with+[18F]+FDG+approaching+that+of+functional+MRI.">Reduced task durations in functional PET imaging with [18F] FDG approaching that of functional MRI.</a> Neuroimage. 181, 323-330 (2018).</li><li>Villien, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dynamic+functional+imaging+of+brain+glucose+utilization+using+fPET-FDG.">Dynamic functional imaging of brain glucose utilization using fPET-FDG.</a> Neuroimage. 100, 192-199 (2014).</li><li>Carson, R. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PET+physiological+measurements+using+constant+infusion.">PET physiological measurements using constant infusion.</a> Nuclear Medicine and Biology. 27 (7), 657-660 (2000).</li><li>Carson, R. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+bolus+and+infusion+methods+for+receptor+quantitation:+application+to+[18F]+cyclofoxy+and+positron+emission+tomography.">Comparison of bolus and infusion methods for receptor quantitation: application to [18F] cyclofoxy and positron emission tomography.</a> Journal of Cerebral Blood Flow &amp; Metabolism. 13 (1), 24-42 (1993).</li><li>National Health and Medical Research Council. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> National statement on ethical conduct in human research. , (2007).</li><li>Australian Radiation Protection and Nuclear Safety Agency. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Code of practice for the exposure of humans to ionizing radiation for research purposes. , (2005).</li><li>Jenkinson, M., Beckmann, C. F., Behrens, T. E., Woolrich, M. W., Smith, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=FSL.">FSL.</a> Neuroimage. 62 (2), 782-790 (2012).</li><li>Tustison, N. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=N4ITK:+improved+N3+bias+correction.">N4ITK: improved N3 bias correction.</a> IEEE Transactions on Medical Imaging. 29 (6), 1310 (2010).</li><li>Avants, B., Klein, A., Tustison, N., Woo, J., Gee, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> 16th Annual Meeting for the Organization of Human Brain Mapping. , (2010).</li><li>Avants, B. B., Epstein, C. L., Grossman, M., Gee, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Symmetric+diffeomorphic+image+registration+with+cross-correlation:+evaluating+automated+labeling+of+elderly+and+neurodegenerative+brain.">Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain.</a> Medical Image Analysis. 12 (1), 26-41 (2008).</li><li>Klein, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mindboggling+morphometry+of+human+brains.">Mindboggling morphometry of human brains.</a> PLoS Computational Biology. 13 (2), e1005350 (2017).</li><li>Tustison, N. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Large-scale+evaluation+of+ANTs+and+FreeSurfer+cortical+thickness+measurements.">Large-scale evaluation of ANTs and FreeSurfer cortical thickness measurements.</a> Neuroimage. 99, 166-179 (2014).</li><li>Avants, B. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+reproducible+evaluation+of+ANTs+similarity+metric+performance+in+brain+image+registration.">A reproducible evaluation of ANTs similarity metric performance in brain image registration.</a> Neuroimage. 54 (3), 2033-2044 (2011).</li><li>Burgos, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Attenuation+correction+synthesis+for+hybrid+PET-MR+scanners:+application+to+brain+studies.">Attenuation correction synthesis for hybrid PET-MR scanners: application to brain studies.</a> IEEE Transactions on Medical Imaging. 33 (12), 2332-2341 (2014).</li><li>Panin, V. Y., Kehren, F., Michel, C., Casey, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fully+3-D+PET+reconstruction+with+system+matrix+derived+from+point+source+measurements.">Fully 3-D PET reconstruction with system matrix derived from point source measurements.</a> IEEE Transactions on Medical Imaging. 25 (7), 907-921 (2006).</li><li>Jenkinson, M., Bannister, P., Brady, M., Smith, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Improved+optimization+for+the+robust+and+accurate+linear+registration+and+motion+correction+of+brain+images.">Improved optimization for the robust and accurate linear registration and motion correction of brain images.</a> Neuroimage. 17 (2), 825-841 (2002).</li><li>Bludau, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cytoarchitecture,+probability+maps+and+functions+of+the+human+frontal+pole.">Cytoarchitecture, probability maps and functions of the human frontal pole.</a> Neuroimage. 93, 260-275 (2014).</li><li>Amunts, K., Malikovic, A., Mohlberg, H., Schormann, T., Zilles, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Brodmann's+areas+17+and+18+brought+into+stereotaxic+space-where+and+how+variable?.">Brodmann's areas 17 and 18 brought into stereotaxic space-where and how variable?.</a> Neuroimage. 11 (1), 66-84 (2000).</li><li>Malikovic, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cytoarchitectonic+analysis+of+the+human+extrastriate+cortex+in+the+region+of+V5/MT+:+a+probabilistic,+stereotaxic+map+of+area+hOc5.">Cytoarchitectonic analysis of the human extrastriate cortex in the region of V5/MT+: a probabilistic, stereotaxic map of area hOc5.</a> Cerebral Cortex. 17 (3), 562-574 (2006).</li><li>Wilms, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Human+V5/MT+:+comparison+of+functional+and+cytoarchitectonic+data.">Human V5/MT+: comparison of functional and cytoarchitectonic data.</a> Anatomy and Embryology. 210 (5-6), 485-495 (2005).</li><li>Eickhoff, S. B., Heim, S., Zilles, K., Amunts, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Testing+anatomically+specified+hypotheses+in+functional+imaging+using+cytoarchitectonic+maps.">Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps.</a> Neuroimage. 32 (2), 570-582 (2006).</li><li>Eickhoff, S. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assignment+of+functional+activations+to+probabilistic+cytoarchitectonic+areas+revisited.">Assignment of functional activations to probabilistic cytoarchitectonic areas revisited.</a> Neuroimage. 36 (3), 511-521 (2007).</li><li>Eickhoff, S. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+SPM+toolbox+for+combining+probabilistic+cytoarchitectonic+maps+and+functional+imaging+data.">A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data.</a> Neuroimage. 25 (4), 1325-1335 (2005).</li><li>Everett, B. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+of+radial+arterial+catheterization+in+PET+research+subjects.">Safety of radial arterial catheterization in PET research subjects.</a> Journal of Nuclear Medicine. 50 (10), 1742-1742 (2009).</li><li>Takagi, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+PET+cerebral+glucose+metabolism+estimates+using+a+single+non-arterialized+venous-blood+sample.">Quantitative PET cerebral glucose metabolism estimates using a single non-arterialized venous-blood sample.</a> Annals of Nuclear Medicine. 18 (4), 297-302 (2004).</li><li>Zanotti-Fregonara, P., Chen, K., Liow, J. S., Fujita, M., Innis, R. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Image-derived+input+function+for+brain+PET+studies:+many+challenges+and+few+opportunities.">Image-derived input function for brain PET studies: many challenges and few opportunities.</a> Journal of Cerebral Blood Flow &amp; Metabolism. 31 (10), 1986-1998 (2011).</li><li>O'Loughlin, S., Currie, G. M., Trifonovic, M., Kiat, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ambient+temperature+and+cardiac+accumulation+of+18F-FDG.">Ambient temperature and cardiac accumulation of 18F-FDG.</a> Journal of Nuclear Medicine Technology. 42 (3), 188-193 (2014).</li></ol>

FDG-PET is a powerful imaging technology that measures glucose uptake, an index of cerebral glucose metabolism. To date, most neuroscience studies using FDG-PET use a traditional bolus administration approach, with a static image resolution that represents the integral of all metabolic activity over the course of the scan2. This manuscript describes two alternative radiotracer administration protocols: the infusion-only (e.g., Villien et al., Jamadar et al.19,<su...

Positron emission tomography (PET) is a powerful molecular imaging technique that is widely used in both clinical and research settings (see Heurling et al.1 for a recent comprehensive review). The molecular targets that can be imaged using PET are only limited by the availability of radiotracers, and numerous tracers have been developed to image neural metabolism receptors, proteins, and enzymes2,3. In neuroscience, one of the most used radiotracers is 18F-fluorodeoxyglucose (FDG-PET), which measures glucose uptake, usually interpreted as an index of cerebral glucose metabolism. The human brain requires a constant and reliable supply of glucose to satisfy its energy requirements4,5, and 70-80% of cerebral glucose metabolism is used by neurons during synaptic transmission6. Changes to cerebral glucose metabolism are thought to initiate and contribute to numerous conditions, including psychiatric, neurodegenerative, and ischemic conditions7,8,9. Furthermore, as FDG uptake is proportional to synaptic activity10,11,12, it is considered a more direct and less confounded index of neuronal activity compared to the more widely used blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) response. BOLD-fMRI is an indirect index of neural activity and measures changes in deoxygenated hemoglobin that occur following a cascade of neurovascular changes following neuronal activity.
Most FDG-PET studies of the human brain acquire static images of cerebral glucose uptake. The participant rests quietly for 10 min with their eyes open in a darkened room. The full radiotracer dose is administered as a bolus over a period of seconds, and the participant then rests for a further 30 min. Following the uptake period, participants are placed in the center of the PET scanner, and a PET image that reflects the cumulative FDG distribution over the course of the uptake and scanning periods is acquired. Thus, the neuronal activity indexed by the PET image represents the cumulative average of all cognitive activity over uptake and scan periods and is not specific to cognitive activity during the scan. This method has provided great insight into the cerebral metabolism of the brain and neuronal function. However, the temporal resolution is equal to the scan duration (often ~45 min, effectively yielding a static measurement of glucose uptake; this compares unfavourably to neuronal response during cognitive processes and common experiments in neuroimaging. Due to the limited temporal resolution, the method provides a non-specific index of glucose uptake (i.e., not locked to a task or cognitive process) and cannot provide measures of within-subject variability, which can lead to erroneous scientific conclusions due to Simpson&#39;s Paradox13. Simpson&#8217;s Paradox is a scenario, where brain-behavior relationships calculated across-subjects are not necessarily indicative of the same relationships tested within-subjects. Furthermore, recent attempts to apply functional connectivity measures to FDG-PET can only measure across-subjects connectivity. Thus, differences in connectivity can only be compared between groups and cannot be calculated for individual subjects. While it is debatable what exactly across-subject connectivity measures14, it is clear that measures calculated across-but not within-subjects cannot be used as a biomarker for disease states or used to examine the source of individual variation.
In the past five years, the development and wider accessibility of clinical-grade simultaneous MRI-PET scanners has sparked renewed research interest in FDG-PET imaging2 in cognitive neuroscience. With these developments, researchers have focused on improving the temporal resolution of FDG-PET to approach the standards of BOLD-fMRI (~0.5&#8722;2.5 s). Note that the spatial resolution of BOLD-fMRI can approach submillimeter resolutions but the spatial resolution of FDG-PET is fundamentally limited to around 0.54 mm full width at half maximum (FWHM) due to the positron range15. Dynamic FDG-PET acquisitions, which are often used clinically, use the bolus administration method and reconstruct the list-mode data into bins. The bolus dynamic FDG-PET method offers a temporal resolution of around 100 s (e.g., Tomasi et al.16). This is clearly much better compared to static FDG-PET imaging but is not comparable to BOLD-fMRI. Additionally, the window in which brain function may be examined is limited, because the blood plasma concentration of FDG diminishes soon after the bolus is administered.
To expand this experimental window, a handful of studies17,18,19,20,21 have adapted the radiotracer infusion method previously proposed by Carson22,23. In this method, sometimes described as &#39;functional FDG-PET&#39; (FDG-fPET, analogous to BOLD-fMRI), the radiotracer is administered as a constant infusion over the course of the entire PET scan (~90 min). The goal of the infusion protocol is to maintain a constant plasma supply of FDG to track dynamic changes in glucose uptake across time. In a proof-of-concept study, Villien et al.21 used a constant infusion protocol and simultaneous MRI/FDG-fPET to show dynamic changes in glucose uptake in response to checkerboard stimulation with a temporal resolution of 60 s. Subsequent studies have used this method to show task-locked FDG-fPET (i.e., time-locked to an external stimulus19) and task-related FDG-fPET (i.e., not time-locked to an external stimulus17,18) glucose uptake. Using these methods, FDG-fPET temporal resolutions of 60 s have been obtained, which is a substantial improvement over bolus methods. Preliminary data show that the infusion method can provide temporal resolutions of 20&#8722;60 s19.
Despite the promising results from the constant infusion method, the plasma radioactivity curves of these studies show that the infusion method is not sufficient to reach a steady-state within the timeframe of a 90 min scan19,21. In addition to the constant infusion procedure, Carson22 also proposed a hybrid bolus/infusion procedure, where the goal is to quickly reach equilibrium at the beginning of the scan, and then sustain plasma radioactivity levels at equilibrium for the duration of the scan. Rischka et al.20 recently applied this technique using a 20% bolus plus 80% infusion. As expected, the arterial input function quickly rose above baseline levels and was sustained at a higher rate for a longer time, compared to results using an infusion-only procedure19,21.
This paper describes the acquisition protocols for acquiring high temporal resolution FDG-fPET scans using infusion-only and bolus/infusion radiotracer administration. These protocols have been developed for use in a simultaneous MRI-PET environment with a 90&#8722;95 min acquisition time19. In the protocol, blood samples are taken to quantify plasma serum radioactivity for subsequent quantification of PET images. While the protocol&#39;s focus is the application of infusion methods for functional neuroimaging using BOLD-fMRI/FDG-fPET, these methods can be applied to any FDG-fPET study regardless of whether simultaneous MRI, BOLD-fMRI, computed tomography (CT), or other neuroimages are acquired. Figure 1 shows the flowchart of procedures in this protocol.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Blood Collection Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>--12-15 vacutainers</td>
			<td>Becton Dickinson, NJ USA</td>
			<td>364880</td>
			<td>Remain in sterile packaging until required to put blood in tube</td>
		</tr>
		<tr>
			<td>--12-15 10mL LH blood collecting tubes</td>
			<td>Becton Dickinson</td>
			<td>367526</td>
			<td>Marked with the sample number (e.g., S1, S2&#8230;) and subsequently marked with the sample time (e.g., time 0 + x min [T0+x])</td>
		</tr>
		<tr>
			<td>--2-15 10mL Terumo syringe</td>
			<td>Terumo Tokyo, Japan</td>
			<td>SS+10L</td>
			<td>These are drawn up on the day of the study and capped with the ampoule that contained the saline</td>
		</tr>
		<tr>
			<td>-- pre-drawn 0.9% saline flushes</td>
			<td>Pfizer, NY, USA</td>
			<td>61039117</td>
			<td></td>
		</tr>
		<tr>
			<td>--12-15 5mL Terumo syringes</td>
			<td>Terumo Tokyo, Japan</td>
			<td>SS+05S</td>
			<td>Remain in sterile packaging until ready to withdraw a blood sample</td>
		</tr>
		<tr>
			<td>Safety &#38; Waste Equipment</td>
			<td></td>
			<td></td>
			<td>All objects arranged on a plastic chair inside the scanner room on the same side as the arm from which the blood samples will be taken. Biohazard and non-biohazard waste bags to be used. Gloves and waste bags to be easily accessible when preparing the radioactivity in the dispensing area and when pipetting the plasma samples. Biohazard and non-biohazard waste bags to be used. All waste generated is checked with the Geiger counter to ensure that radioactive contaminated waste is stored until it is safe to be disposed of according to Australian Radiation Protection and Nuclear Safety Agency (APRANSA) guidelines for Radiation protection series No.6 (2017).</td>
		</tr>
		<tr>
			<td>-- Gloves</td>
			<td>Westlab, VIC, Australia</td>
			<td>663-219</td>
			<td></td>
		</tr>
		<tr>
			<td>-- waste bags</td>
			<td>Austar Packaging, VIC, Australia</td>
			<td>YIW6090</td>
			<td></td>
		</tr>
		<tr>
			<td>--cello underpads &#8216;blueys&#8217; Underpads 5 Ply</td>
			<td>Halyard Health, NSW, Australia</td>
			<td>2765A</td>
			<td></td>
		</tr>
		<tr>
			<td>--Blue Sharpie pen</td>
			<td>Sharpie, TN, USA</td>
			<td>S30063</td>
			<td></td>
		</tr>
		<tr>
			<td>Dose Syringes</td>
			<td></td>
			<td></td>
			<td>Remain in sterile packaging until ready for use. All syringes used in this facility have an additional 20% volume capacity above the stated volume on the packaging. This is important for the 50mL syringe where the total capacity of 60mL is used</td>
		</tr>
		<tr>
			<td>--5mL</td>
			<td>Terumo Tokyo, Japan</td>
			<td>SS+05S</td>
			<td></td>
		</tr>
		<tr>
			<td>-- 20mL</td>
			<td>Terumo Tokyo, Japan</td>
			<td>SS+20L</td>
			<td></td>
		</tr>
		<tr>
			<td>--50mL</td>
			<td>Terumo Tokyo, Japan</td>
			<td>SS*50LE</td>
			<td></td>
		</tr>
		<tr>
			<td>--1 Terumo 18-gauge needle</td>
			<td>Terumo Tokyo, Japan</td>
			<td>NN+1838R</td>
			<td>Remain in sterile packaging until ready to inject [18F]FDG into the saline bag</td>
		</tr>
		<tr>
			<td>--100mL 0.9% saline bag</td>
			<td>Baxter Pharmaceutical, IL, USA</td>
			<td>AHB1307</td>
			<td>Remain in sterile packaging until ready to inject [18F]FDG</td>
		</tr>
		<tr>
			<td>Radiochemistry Lab Supplies</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>--Heraeus Megafuge 16 centrifuge; Rotor Bioshield 720</td>
			<td>ThermoScientific MA, USA</td>
			<td>75004230</td>
			<td>Relative Centrifugal Force = 724 Our settings are 2000RPM for 5mins. Acceleration and deceleration curves set to 8</td>
		</tr>
		<tr>
			<td>--Single well counter</td>
			<td>Laboratory Technologies, Inc. IL, USA</td>
			<td>630-365-1000</td>
			<td>Complete daily quality control (includes background count) and protocol set to 18F and 4mins. Cross calibration is performed between the well counter, dose calibrator and scanner on a bi-monthly basis.</td>
		</tr>
		<tr>
			<td>--Pipette</td>
			<td>ISG Xacto, Vienna, Austria</td>
			<td>LI10434</td>
			<td>We use a 100-1000 &#956;L set to 1000&#956;L. It is calibrated annually.</td>
		</tr>
		<tr>
			<td>--12-15 plasma counting tubes</td>
			<td>Techno PLAS; SA Australia</td>
			<td>P10316SU</td>
			<td>Marked in the same manner as the LH blood tubes</td>
		</tr>
		<tr>
			<td>--12-15 pipette tips</td>
			<td>Expell Capp, Denmark</td>
			<td>5130140-1</td>
			<td></td>
		</tr>
		<tr>
			<td>--3 test tube racks</td>
			<td>Generic</td>
			<td></td>
			<td>Checked with a Geiger counter to ensure there is no radiation contamination on them</td>
		</tr>
		<tr>
			<td>--500mL volumetric flask and distilled water</td>
			<td>Generic</td>
			<td></td>
			<td>Need approximately 500mL of distilled water to prepare the reference for gamma counting</td>
		</tr>
		<tr>
			<td>--Synchronised clocks in scanner room, console and radiochemistry lab</td>
			<td>Generic</td>
			<td></td>
			<td>Synchronisation checks are routinely completed in the facility on a weekly basis</td>
		</tr>
		<tr>
			<td>--Haemoglobin Monitor</td>
			<td>EKF Diagnostic Cardiff, UK Haemo Control.</td>
			<td>3000-0810-6801</td>
			<td>Manufacturer recommended quality control performed before testing on participant&#8217;s blood sample.</td>
		</tr>
		<tr>
			<td>--Glucometre</td>
			<td>Roche Accu-Chek</td>
			<td>6870252001</td>
			<td>Accu-Chek Performa is used to measure participant blood sugar levels in mmol/L. Quality control is performed daily using high and low concentration solution control test.</td>
		</tr>
		<tr>
			<td>Cannulating Equipment</td>
			<td></td>
			<td></td>
			<td>Check expiry dates and train NMT to prepare aseptically for cannulation.</td>
		</tr>
		<tr>
			<td>--Regulation tourniquet</td>
			<td>CBC Classic Kimetec GmBH</td>
			<td>K5020</td>
			<td></td>
		</tr>
		<tr>
			<td>--20, 22 and 24 gauge cannulas</td>
			<td>Braun, Melsungen Germany</td>
			<td>4251644-03; 4251628-03; 4251601-03</td>
			<td></td>
		</tr>
		<tr>
			<td>--tegaderm dressings</td>
			<td>3M, MN USA</td>
			<td>1624W</td>
			<td></td>
		</tr>
		<tr>
			<td>--alcohol and chlorhexidine swabs</td>
			<td>Reynard Health Supplies, NSW Australia</td>
			<td>RHS408</td>
			<td></td>
		</tr>
		<tr>
			<td>--0.9% saline 10mL ampoules; for flushes</td>
			<td>Pfizer, NY, USA</td>
			<td>61039117</td>
			<td></td>
		</tr>
		<tr>
			<td>--10mL syringes</td>
			<td>Terumo Tokyo, Japan</td>
			<td>SS+10L</td>
			<td></td>
		</tr>
		<tr>
			<td>--3-way tap</td>
			<td>Becton Dickinson Connecta</td>
			<td>394600</td>
			<td></td>
		</tr>
		<tr>
			<td>--IV bung</td>
			<td>Safsite Braun PA USA</td>
			<td>415068</td>
			<td></td>
		</tr>
		<tr>
			<td>--Optional extension tube, microbore extension set</td>
			<td>M Devices, Denmark</td>
			<td>IV054000</td>
			<td></td>
		</tr>
		<tr>
			<td>Scanner Room Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>--Siemens Biograph 3T mMR</td>
			<td>Siemens, Erlangen, Germany</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>--Portable lead barrier shield</td>
			<td>Gammasonics</td>
			<td>Custom-built</td>
			<td>MR-conditional lead barrier shield. Positioned at the 2000 Gauss line with the castors locked to provide additional shielding of the radioactivity connected to the infusion pump.</td>
		</tr>
		<tr>
			<td>--Infusion pump BodyGuard 323 MR-conditional infusion pump</td>
			<td>Caesarea Medical Electronics</td>
			<td>300-040XP</td>
			<td>MR-compatible. This model is cleared for use on 1.5 and 3T scanners at 2000 Gauss with castors locked.</td>
		</tr>
		<tr>
			<td>--Infusion pump tubing</td>
			<td>Caesarea Medical Electronics</td>
			<td>100-163X2YNKS</td>
			<td>Tubing is administration set with an anti-siphon valve and male luer lock (REF 100-163X2YNKS).</td>
		</tr>
		<tr>
			<td>--Lead bricks</td>
			<td>Custom built</td>
			<td></td>
			<td>Tested for ferromagnetic translational force</td>
		</tr>
		<tr>
			<td>Other Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>--Syringe shields</td>
			<td>Biodex, NY USA</td>
			<td>Custom-built</td>
			<td>There is a 5mL tungsten syringe shield that is MR-safe, as well as a 50mL lead shield that has been tested for ferromagnetic attraction prior to use in the MR-PET scanner. It is used to transport the radioactive dose from the radiochemistry lab into the scanner to minimise radiation exposure to the NMT.</td>
		</tr>
		<tr>
			<td>--Geiger counter Model 26-1 Integrated Frisker</td>
			<td>Ludlum Measurements, Inc. TX USA</td>
			<td>48-4007</td>
			<td>This is calibrated annually and used to monitor potential contamination and waste. It is not taken into the MR-PET scanner.</td>
		</tr>
	</tbody>
</table>

radiotracer administration for high temporal resolution positron emission tomography of the human brain: application to fdg-fpet

Functional positron emission tomography (fPET) provides a method to track molecular targets in the human brain. With a radioactively-labelled glucose analogue, 18F-fluordeoxyglucose (FDG-fPET), it is now possible to measure the dynamics of glucose metabolism with temporal resolutions approaching those of functional magnetic resonance imaging (fMRI). This direct measure of glucose uptake has enormous potential for understanding normal and abnormal brain function and probing the effects of metabolic and neurodegenerative diseases. Further, new advances in hybrid MR-PET hardware make it possible to capture fluctuations in glucose and blood oxygenation simultaneously using fMRI and FDG-fPET.
The temporal resolution and signal-to-noise of the FDG-fPET images is critically dependent upon the administration of the radiotracer. This work presents two alternative continuous infusion protocols and compares them to a traditional bolus approach. It presents a method for acquiring blood samples, time-locking PET, MRI, experimental stimulus, and administering the non-traditional tracer delivery. Using a visual stimulus, the protocol results show cortical maps of the glucose-response to external stimuli on an individual level with a temporal resolution of 16 s.

Study-specific methods 
Here, study-specific details for the representative results are reported. These details are not critical to the procedure and will vary across studies.
Participants and task design 
Participants (n = 3, Table 2) underwent a simultaneous BOLD-fMRI/FDG-fPET study. As this manuscript focuses on the PET acquisition protocol, MRI re...

Watch this Scientific Journal Video about Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET at JoVE.com

Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET

This manuscript describes two radiotracer administration protocols for FDG-PET (constant infusion and bolus plus infusion) and compares them to bolus administration. Temporal resolutions of 16 s are achievable using these protocols.

Functional positron emission tomography (fPET) provides a method to track molecular targets in the human brain. With a radioactively-labelled glucose ...

Research

JoVE Journal

Behavior

Stereotactic Injection of MicroRNA-expressing Lentiviruses to the Mouse Hippocampus CA1 Region and Assessment of the Behavioral Outcome

MicroRNAs (miRNAs) are small regulatory single-stranded RNA molecules around 22 nucleotides long that may each target numerous mRNA transcripts and dim an ...

Uncovering Beat Deafness: Detecting Rhythm Disorders with Synchronized Finger Tapping and Perceptual Timing Tasks

A set of behavioral tasks for assessing perceptual and sensorimotor timing abilities in the general population (i.e., non-musicians) is presented here ...

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been ...

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people.  There is a need ...

Application of MultiColor FlpOut Technique to Study High Resolution Single Cell Morphologies and Cell Interactions of Glia in Drosophila

Application of MultiColor FlpOut Technique to Study High Resolution Single Cell Morphologies and Cell Interactions of Glia in Drosophila

Cells display different morphologies and complex anatomical relationships. How do cells interact with their neighbors? Do the interactions differ between ...

An Automated T-maze Based Apparatus and Protocol for Analyzing Delay- and Effort-based Decision Making in  Free Moving Rodents

Many neurological and psychiatric patients demonstrate difficulties and/or deficits in decision making. Rodent models are helpful to produce a deeper ...

Using Eye Movements Recorded in the Visual World Paradigm to Explore the Online Processing of Spoken Language

In a typical eye tracking study using the visual world paradigm, participants' eye movements to objects or pictures in the visual workspace are recorded ...

Using the Visual World Paradigm to Study Sentence Comprehension in Mandarin-Speaking Children with Autism

Sentence comprehension relies on the ability to rapidly integrate different types of linguistic and non-linguistic information. However, there is ...

Application of 3D Printing in the Construction of Burr Hole Ring for Deep Brain Stimulation Implants

3D printing has been widely applied in the medical field since the 1980s, especially in surgery, such as preoperative simulation, anatomical learning and ...

Human Circadian Phenotyping and Diurnal Performance Testing in the Real World

In our continuously developing &#39;around the clock&#39; society, there is a need to increase our understanding of how changes in biology, physiology and ...