PET measurement of changes in D2/D3 dopamine receptor binding in a nonhuman primate during chronic deep brain stimulation of the bed nucleus of the stria terminalisIntroductionExperimental proceduresDBS surgery and stimulation parametersTiming of PET scans and stimulation parameter changesAnimal care proceduresPET scansImage processingResultsDiscussionConclusionAcknowledgementsReferencesJournal of Neuroscience Methods 176 (2009) 129–135Contents lists available at ScienceDirectJournal of Neuroscience Methodsjournal homepage: www.elsevier.com/locate/jneumethPET measurement of changes in D2/D3 dopamine receptor binding in anonhuman primate during chronic deep brain stimulationof the bed nucleus of the stria terminalisNicholas T. Vandeheya, P. Charles Garellb, Joseph A. Hampelc, Dhanabalan Muralic,Elizabeth M. Smitha, Richard Davidsonc, Alexander K. Conversec,R. Jerry Nicklesa, Bradley T. Christiana,c,∗aUniversity of Wisconsin-Madison, Department of Medical Physics, United StatesbNew York Medical College, Department of Neurosurgery, United StatescUniversity of Wisconsin-Madison, Waisman Laboratory for Brain Imaging and Behavior, United Statesarticle infoArticle history:Received 21 April 2008Received in revised form 27 August 2008Accepted 27 August 2008Keywords:Deep brain stimulationDBSPETBNSTD2/D3DopamineFallyprideabstractPET imaging is a powerful tool for measuring physiological changes in the brain during deep brain stimu-lation (DBS). In this work, we acquired five PET scans using a highly selective D2/D3 dopamine antagonist,18F-fallypride, to track changes in dopamine receptor availability, as measured by the distribution volumeratio (DVR), through the course of DBS in the bed nucleus of the stria terminalis (BNST) in a nonhumanprimate.Methods: PET scans were performed on a rhesus monkey with unilateral BNST stimulation during periodsof baseline, chronic high frequency (130 Hz) and low frequency (50 Hz) DBS stimulation, and during awashout period between stimulation periods. A final scan was performed with the electrode stimulationstarting 110 min into the scan. Whole brain parametric images of18F-fallypride DVR were calculated foreach condition to track changes in both striatal and extrastriatal D2/D3 availability.Results: The monkey displayed significant increases in receptor binding throughout the brain during DBSrelative to baseline for 130 and 50 Hz, with changes in DVR of: caudate 42%, 51%; putamen 56%, 57%;thalamus 33%, 49%; substantia nigra 29%, 26%; and prefrontal cortex 28%, 56%, respectively. Washout andpost-stimulation scans revealed DVR values close to baseline values. Activating the stimulator midwaythrough the final scan resulted in no statistically significant changes in binding.Conclusions: PET neuroligand imaging has demonstrated the sensitivity to track changes in dopamineD2/D3 binding during the course of DBS. These methods show great potential for providing insight intothe neurochemical consequences of DBS.© 2008 Elsevier B.V. All rights reserved.1. IntroductionDeep brain stimulation (DBS) of the subthalamic nucleus, globuspallidus or thalamus are clinically used methods for effectivealleviation of symptoms associated with movement disorderssuch as Parkinson’s disease, essential tremor, and dystonia. DBShas also been used experimentally in attempts to treat epilepsy,depression, obsessive–compulsive disorder, cluster headache, andmost recently, obesity (Leone et al., 2005; Mayberg et al., 2005;∗Corresponding author at: University of Wisconsin-Madison, T235 WaismanCenter, 1500 Highland Avenue, Madison, WI 53705, United States.Tel.: +1 608 890 0750.E-mail address: [email protected] (B.T. Christian).Perlmutter and Mink, 2006; Sani et al., 2007; Lacan et al., 2008;Hamani et al., 2008). Despite its many uses, the mechanisms of DBSeffectiveness remain unclear (McIntyre et al., 2004; Montgomeryand Gale, 2008). Much of the current research in DBS uses elec-trical recording on the cellular level, but a more systems levelapproach, such as molecular imaging, shows promise as a researchtool for understanding the neurochemical changes accompanyingDBS treatment.Functional imaging using positron emission tomography (PET)has been used to investigate the effects of DBS in a variety of exper-iments. Using15O–H2O as a tracer to measure changes in regionalblood flow in essential tremor patients, Perlmutter et al. (2002)found that thalamic stimulation increased blood flow in targetsdownstream of the thalamus. Also using15O–H2O, Haslinger et al.(2005) examined patients with DBS of the ventralis intermedius,0165-0270/$ – see front matter © 2008 Elsevier B.V. All rights reserved.doi:10.1016/j.jneumeth.2008.08.033130 N.T. Vandehey et al. / Journal of Neuroscience Methods 176 (2009) 129–135measuring increases in blood flow at the stimulation site and sen-sory motor cortex, both correlated with stimulus frequency andstimulus amplitude. Other PET research has used18F-FDG to mea-sure regional metabolism during DBS. Fukuda et al. (2001) observedmetabolic changes correlated with changes in the Unified Parkin-sons Disease Rating Scale scores during pallidal DBS, while Hilker etal. (2004) found that DBS of the subthalamic nucleus activates thestimulated target while altering non-motor circuits. Furthermore,the experiments by Schlaepfer et al. (2007) showed that DBS of thenucleus accumbens alters metabolism in a distributed network oflimbic and prefrontal brain regions.To gain further insight into the physiological mechanisms ofDBS, beyond regional perfusion and metabolism, neuroligand PETmethods offer great potential to examine specific biochemical pro-cesses during DBS. The dopaminergic neuroreceptor system is ofparticular interest with DBS treatment of movement disorders. Sev-eral PET studies have been conducted to examine the dopaminergicsystem during DBS of the subthalamic nucleus: all three came tothe conclusion that stimulation of the subthalamic nucleus doesnot significantly alter11C-raclopride binding to D2/D3 receptors inthe striatum (caudate and putamen) (Abosch et al., 2003; Hilker etal., 2003; Strafella et al., 2003). However, another study reportedsignificant11C-raclopride binding differences between pre- andpost-DBS surger y groups, suggesting that DBS of the subthala-mic nucleus reduces levadopa-induced fluctuations of synapticdopamine levels in the striatum (Nimura et al., 2005). Despite itsfrequent usage in studying D2/D3 receptor