Poster Sessions 1060. Spinal Cord and Brain Pain FMRI in Rats: Anatomical Sites of Analgesic Action of Buprenorphine on the Noxious Electrical Stimulation-Induced Pain Fuqiang Zhao 1 , Denise Welsh 1 , Mangay Williams 1 , Alexandre Coimbra 1 , Mark O. Urban 2 , Richard Hargreaves 2 , Jeffrey Evelhoch 1 , Donald S. Williams 1 1 Imaging Department, Merck Research Laboratories, West Point, PA, United States; 2 Neuroscience Department, Merck Research Laboratories, West Point, PA, United States To validate the fMRI signals in the spinal cord and the brain of rats induced by noxious stimulation as a pain biomarker, and to determine its utility in elucidation of mechanisms of action of analgesics, the effect of buprenorphine (BPN), a partial ì-opioid agonist, on pain fMRI signals was investigated. The pain fMRI signals in the caudate putamen and thalamus region were totally suppressed, while those in spinal cord, cerebellum, thalamic relay of somatosensory pathway, and primary somatosensory cortex were only partially (if at all) suppressed. Such a suppression pattern is consistent with the density of ì opioid receptor distribution in brain, supporting the idea that fMRI can provide anatomical action sites of the analgesics, which should help to understand their mechanisms of action. 1061. Pharmacologic Resting State-FMRI: Effects of Cannabis on Functional Brain Connectivity ‘at Rest’ Roelof Peter Soeter 1,2 , Linda E. Klumpers 3 , Naj Khalili-Mahani 1,2 , Mark A. van Buchem 1,2 , Serge A.R.B. Rombouts 1,2 , Joop M.A. van Gerven, 3,4 1 Department of Radiology, Leiden University Medical Center (LUMC), Leiden, Netherlands; 2 Leiden Institute for Brain and Cognition (LIBC), Leiden, Netherlands; 3 Centre for Human Drug Research, Leiden, Netherlands; 4 Department of Neurology, Leiden University Medical Center (LUMC), Leiden, Netherlands ‘Resting state’ FMRI is a promising technique for drug studies, because it allows a repeated task-independent assessment of functional interactions between brain regions (functional connectivity). Here we investigate the effects of THC, the psychoactive compound of cannabis, on functional brain connectivity. Nine healthy male volunteers participated in a randomised, double blind, placebo-controlled trial in which 8 RS-FMRI scans were obtained in each treatment occasion. THC administration decreased connectivity in different brain regions, including cerebellum and several cortical regions. Functional connectivity using RS-FMRI is a promising new technique to study pharmacologically induced changes in brain activity. 1062. On the Complexity of the BOLD Response to Painful Heat, Relationship of the Response with Self- Assessment of Pain and Implications for FMRI Sensitivity to Analgesic Treatment Alexandre Coimbra 1,2 , Richard Baumgartner, 2,3 , Sonya Apreleva, 2,3 , Jaymin Upadhyay, 2,4 , Adam Schwarz, 2,5 , Julie Anderson, 2,4 , Lauren Nutile, 2,4 , Gautam Pendse, 2,4 , James Bishop, 2,4 , Ed George, ,2,4 , Smiriti Iyengar, 2,5 , David Bleakman, 2,5 , Richard Hargreaves, 2,6 , Jeff Evelhoch 1,2 , Lino Becerra, 2,4 , David Borsook, 2,4 1 Imaging, Merck Research Laboratories, West Point, PA, United States; 2 Imaging Consortium for Drug Development, Belmont, MA, United States; 3 Biometrics, Merck Research Laboratories, Rahway, NJ, United States; 4 PAIN, McLean Group, Belmont, MA, United States; 5 Lilly Research Laboratories, Indianapolis, IN, United States; 6 Neurosciences, Merck Research Laboratories, West Point, PA, United States The complexity of the experience of pain is reflected in the functional MRI BOLD response to painful stimuli. Several publications reported on a biphasic BOLD response composed of an early phase closely locked with stimulus time, and a late phase which some have suggested is related to self-assessment of pain. In a placebo controlled study of painful heat, the GLM approach was used to generate quantitative measures and address the issue of sensitivity of these endpoints to Buprenorphine treatment (BUP); with a focus on endpoints related to early, stimulus-locked, and late phase modeled by self-assessment. 1063. Repeated Resting State FMRI During Dose-Controlled Morphine and Alcohol Infusion Reveals Localized and Drug Specific Changes in Functional Brain Connectivity Najmeh Khalili-Mahani 1,2 , Remco W. M Zoethout 3 , Christian F. Beckmann 4,5 , Evelinda Baerends 6 , Roelof P. Soeter, 2,6 , Marike de Kam 3 , Mark A. Van Buchem 6 , Joop M. A. Van Gerven 3 , Serge A. R .B. Rombouts, 2,6 1 Leiden University Medical Center, Department of Radiology, Leiden , Netherlands; 2 Leiden Institute for Brain and Cognition, Department of Psychology, Leiden, Netherlands; 3 Center for Human Drug Research, Leiden University Medical Center, Leiden, Netherlands; 4 Oxford University, Oxford, United Kingdom; 5 Imperial College London, London, United Kingdom; 6 Leiden University Medical Center, Department of Radiology, Leiden, Netherlands Using state of art pharmacological infusion techniques in a placebo-controlled two-way (treatment by time: 3x7) repeated measure study we show specific and meaningful variations in resting-state brain connectivity in response to dose-controlled administration of morphine and alcohol 1064. Focal and Drug-Specific Changes in Cerebral Blood Flow in Response to Dose-Controlled Infusion of Alcohol and Morphine in Healthy Young Men Najmeh Khalili-Mahani 1,2 , Mathiass J. P. Van Osch 1 , Remco W. M Zoethout 3 , Evelinda Baerends 1 , Mark A. Van Buchem 1 , Joop M. A. Van Gerven 3 , Serge A. R. B. Rombouts 1,2 1 Leiden University Medical Center, Department of Radiology, Leiden, Netherlands; 2 Leiden Institute for Brain and Cognition, Department of Psychology, Leiden, Netherlands; 3 Center for Human Drug Research, Leiden University Medical Center, Leiden, Netherlands In a within-subject placebo-controlled pharma-fMRI study, we use pseudo-continuous ASL to show localized and drug-specific changes in CBF in response to dose-controlled infusion of morphine and alcohol. Results correspond to variations observed in the resting-state BOLD fluctuations in the same study.
Poster Sessions 1065. Levo-Tetrahydropalmatine Treatment Attenuates Heroin-Priming Induced BOLD Responses in Heroin-Dependent Rats Xiping Liu 1 , Zheng Yang 2 , Jun Xie 3 , Qian Yin 1 , Shi-Jiang Li 1 1 Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States; 2 Beijing Institute of Basic Medical Science, China; 3 GE Healthcare, United States Levo-tetrahydropalmatine (l-THP), purified from the Chinese herb, Stephanie, recently has been demonstrated to be effective in attenuating heroin craving and relapse in heroin addicts; it also inhibits cocaine¡¯s rewarding effects on animal models. Despite this behavioral evidence, the treatment mechanisms of l-THP for drug addiction have yet to be elucidated. Here, we applied high-field pharmacological MRI (phMRI) on heroin-dependent rats with or without chronic l-THP treatment. We found l-THP significantly attenuates heroin-priming induced BOLD responses in heroin-dependent rats in multiple addiction relevant neural circuitries. 1066. Pharmacological Analysis in Experimental Lung Fibrosis Performed by MRI Anna Louise Babin 1 , Catherine Cannet 1 , Christelle Gerard 1 , Clive P. Page 2 , Nicolau Beckmann 1 1 Global Imaging Group, Novartis Institutes for BioMedical Research, Basel, BS, Switzerland; 2 Sackler Institute of Pulmonary Pharmacology, King's College, London, SE1 1UL, United Kingdom Experimental studies of lung fibrosis in animals have usually examined the effects of treatments starting before or at the time of lung injury. However, treatment in humans only begins after disease has been established. Since timing of treatment initiation is critical in this chronic model, we used MRI to assess non-invasively the effects of steroids (budesonide and dexamethasone) in the lungs of bleomycin (BLM) treated rats. MRI relying on non-ionizing radiation opens new avenues in testing compounds in vivo as the responses at several time points during the course of treatment can be easily compared. 1067. Tumor-Targeted Imaging and Delivery of SiRNA Zdravka Medarova 1 , Mohanraja Kumar 1 , Anna Moore 1 1 Molecular Imaging Lab, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States Since their discovery in 1998, small interfering RNAs (siRNAs) have emerged as a powerful new tool for post-transcriptional gene silencing. Here, we describe the synthesis and testing of a tumor-targeted nanoparticle probe (MN-EPPT-siSurvivin) to specifically shuttle siRNA to tumor cells. The probe binds the tumor antigen uMUC-1, found on a range of adenocarcinomas, and useful as an imaging target. Human breast, pancreatic, and colorectal cancer cells took up high amounts of the probe. The uptake could be measured by MRI and resulted in significant knock-down of the target gene. 1068. A Novel Mitochondrial Peptide Causes Recovery of Skeletal Muscle After Burn Trauma as Assessed with P31 NMR and Electron Paramagnetic Resonance in Vivo Valeria Righi 1,2 , Caterina Constantinou, 1,3 , Dionyssios Mintzopoulos 1,2 , Nadeem Khan 4 , Sriram P. Mupparaju 4 , Harold M. Swartz 4 , Hazel H. Szeto 5 , Ronald G. Tompkins 6 , Laurence G. Rahme 3 , A Aria Tzika 1,2 1 NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, Boston, MA, United States; 2 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, United States; 3 Molecular Surgery Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, Boston, MA, United States; 4 EPR Center for Viable Systems, Department of Diagnostic Radiology, Dartmouth Medical School, Hanover, NH, United States; 5 Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, United States; 6 Department of Surgery, Division of Burn, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, Boston, MA, United States Using P31 NMR and Electron Paramagnetic Resonance (EPR) in vivo, we evaluated the effects of a novel (Szeto-Schiller) SS-31 peptide on ATP synthesis rate and redox status, respectively in a clinically relevant burn trauma model. Our results showed that SS-31 peptide induces ATP synthesis rate and causes recovery of the mitochondrial redox status at 6 hours after burn. Thus, EPR, can be used to complement NMR in investigating, and even validating novel mitochondrial agents for burn trauma and a variety of pathologies (i.e., stroke, heart failure, diabetes, degenerative disorders, trauma, cancer) associated with mitochondrial dysfunction, including normal aging. 1069. A Texture Analysis Approach to Quantify Ventilation Changes in Hyperpolarised 3 He MRI of the Rat Lung in an Asthma Model Frank Risse 1 , Jelena Pesic 1 , Simon Young 2 , Lars E. Olsson 1 1 DECS Imaging & Antibodies, AstraZeneca R&D, Mölndal, Sweden; 2 Bioscience, AstraZeneca R&D, Charnwood, United Kingdom The effect of steroid (budesonide) treatment on lung inflammation in rats caused by ovalbumin can be visualised using hyperpolarised 3 He MRI. The aim was to quantify the changes in lung ventilation in this asthma model using texture analysis. Four groups were investigated: controls, vehicle-treated, low and high dose budesonide-treated. First-order texture, geometrical features and features based on second-order statistics using run-length and grey-level cooccurrence matrices were calculated. Additionally, wavelet transforms were applied to compute first-order statistics on multiple scales. The texture analysis showed significant differences between the untreated and the budesonide-treated groups, which was in agreement with a biological marker.
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