Assessment of rodent brain activity using combined [15O]H2O-PET and BOLD-fMRI
Introduction
The study of the functional processes of the brain is of high interest for basic research and for clinical diagnosis. Positron emission tomography (PET) (Frackowiak and Friston, 1994) using [15O]H2O (half-life time T1/2 = 122 s) as a marker for cerebral blood flow (CBF) to map brain activation has been widely employed to investigate brain function in humans (Fox and Mintun, 1989, Fox and Raichle, 1986, Hummel et al., 2009, Payoux et al., 2010) because it allows a rapid alteration between baseline and activation scans due to the short half-life of [15O]. The blood oxygen level dependent effect (BOLD), which has been used more recently in functional magnetic resonance imaging (fMRI) studies of brain activation, reflects the complex interplay between changes in CBF, cerebral blood volume (CBV), cerebral metabolic rate of oxygen consumption (CMRO2) and oxygen extraction fraction (OEF) (Buxton, 2010). Despite the widespread utilization of the BOLD effect to measure brain activation in humans (Brown et al., 2011, Iannetti and Wise, 2007, Luijten et al., 2011) and in animals (Just et al., 2010, Sanganahalli et al., 2008, Seehafer et al., 2010), its physiological bases are not entirely understood (Buxton, 2010, Logothetis et al., 2001, Shulman et al., 2007). Thus, it would be of the utmost interest to measure and compare brain activation using both [15O]H2O-PET and BOLD-fMRI to cross-validate these two markers of brain function and to deconvolute the complex nature of the BOLD signal.
Brain activation studies in rodents undergoing sensory stimulation and assessed using PET in combination with the tracer [15O]H2O have, to the best of our knowledge, not been previously described. There have been a few CBF measurements performed in rats using PET, and most examine global values (Ose et al., 2012, Watabe et al., 2013, Yee et al., 2005). Previous studies comparing PET and BOLD-fMRI have only been performed in humans and have produced contradictory results. Ramsey and colleagues compared [15O]H2O-PET with BOLD-fMRI in sequential measurements, where they identified a high correlation in terms of sensitivity between the two methods (Ramsey et al., 1996). Kinahan et al. found a significant mismatch in spatial location between the PET and fMRI activation centers in humans (Kinahan and Noll, 1999). In addition, Joliot et al. also found a mismatch between the PET and fMRI activation maps in humans (Joliot et al., 1999), whereas a subsequent experiment by Devlin et al. concluded similar, but not identical, PET and fMRI results (Devlin et al., 2000).
To shed additional light on to the relationship between PET and fMRI activation studies, we used a small animal model, which can be extensively examined under more controlled conditions and multiple repetitions. The aim of this study was to compare [15O]H2O-PET and BOLD-fMRI measurements in rats that were acquired in immediate succession during the same anesthetic session using a whisker stimulus. To achieve this goal, we established a noninvasive in vivo brain activation mapping protocol in small animals using [15O]H2O-PET.
Section snippets
Animal preparation
All of the animal experiments were approved by the local authorities (Regierungspraesidium Tuebingen). Eight male Lewis rats at an age of 17 ± 4 weeks and a weight 358 ± 16 g (Charles River Laboratories, Sulzfeld, Germany) were used in the combined PET and MR brain activation measurements. Each animal was initially anesthetized with a mixture of 1.5% isoflurane vaporized in air at a gas flow rate of 1.0 L/min. The animals were placed head first in a prone position on a multimodality imaging bed
Coregistration accuracy of the PET/MR atlas
The generated PET and MR atlases (Supplementary Fig. 3) showed an overall coregistration accuracy of 0.99 ± 0.63 mm (explained in further detail in Supplementary material S 3.1, Supplementary Fig. 4) when comparing the anatomical landmarks between PET and MR on the basis of 13 profile lines. Highly perfused areas were observed in the cortical and thalamic regions of the brain and in the region of the olfactory system. Excellent consistency in the coregistration between the anatomical MR data and
Discussion
CBF increases during stimulation revealed by PET imaging were in the lower range (9.7 ± 4.8%) compared to the values reported in the literature, which ranged from 12 ± 2% (Martin et al., 2006) to 47 ± 29% (Weber et al., 2003) and are further discussed in the Supplementary material (S 4.1). Deviations in the CBF change from these previous studies may be explained by anesthetic effects and differences in the stimulation method used. Because one of the aims of the study was to establish a protocol for
Conclusions
It was shown that somatosensory brain activation in rats can be studied using noninvasive PET imaging with [15O]H2O particularly in combination with isoflurane anesthesia, which makes longitudinal experiments in the same animals feasible. Alterations of brain activation can be measured in fast succession enabling a practical stimulation paradigm within one imaging session using the short half-life CBF tracer [15O]H2O. The presented [15O]H2O-PET imaging protocol is not only useful for whisker
Acknowledgments
We thank Anke Stahlschmitt, Maren Koenig, Mareike Lehnhoff and Funda Cay for their excellent technical assistance. This study was supported by the German Research Foundation (DFG) Grant PI 771-1/1, the Werner Siemens-Foundation and the Wilhelm Schuler-Foundation. This study is also part of the PhD thesis of Hans F. Wehrl.
Conflict of interest
B.J.P. receives grant/research support from AstraZeneca, Bayer Healthcare, Boehringer-Ingelheim, Bruker, Oncodesign, Merck, Siemens and the
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