Pharmaceutical fMRI
Friday 24 April 2009
Room 310 10:30-12:30


David G. Norris and Alice M. Wyrwicz

10:30 792.

Striatal Dopamine Correlates Brain Activation in Precuneus and Thalamus: A PET-FMRI Study

    Dardo Tomasi1, Nora D. Volkow2,3, Ruiliang L. Wang1, Frank Telang1, Gene-Jack Wang1, Joanna S. Fowler1
Medical Department, Brookhaven National Laboratory, Upton, NY, USA; 2National Institute on Drug Abuse, National Institute on Health, Bethesda, MD, USA; 3National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
    Dopamine (DA) is implicated in the modulation of attention but its specific role is not well understood. Here we assessed the relationship between DA markers [DA D2 receptors (D2R) and transporters (DAT)] in the striatum with PET and brain activation during a parametric visual attention (VA) task (measured with BOLD-fMRI) in healthy controls. Increased DAT and D2R availability in striatum were associated with higher activation of the precuneus (BA 7) and the thalamus. Thus, this study suggests that the DA mesostriatal pathways facilitate attention by modulating the activation of regions in the alerting and orienting pathways of attention.
10:42 793. Caffeine's Effects on Resting-State Oxygen and Glucose Metabolism: A Combined MR and PET Study
    Yufen Chen1, Andrew B. Newberg2, Jiongjiong wang1, Hengyi Rao1, Hongyu An3, Joel Greenberg4, Nancy Wintering2, Victoria Tolles2, John A. Detre1
Center of Functional Neuroimaging, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Radiology, University of North Carolina, Chapel Hill, NC, USA; 4Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
    Caffeine is an adenosine antagonist which affects both blood flow and neural activity. It has been suggested that caffeine could alter the coupling between cerebral blood flow and metabolism. In this study, a combination of FDG-PET and ASL was used to study how caffeine affects resting-state blood flow, glucose and oxygen metabolism. The results show caffeine alters the balance of oxygen and glucose metabolism by significantly decreasing glucose metabolic rate. This change was especially prominent in the anterior cingulate, which may explain how caffeine affects alertness.
10:54 794. fMRI of Cocaine Self-Administration in Non-Human Primates
    Ji-Kyung Choi1, Helen Deng1, Wim Vanduffel1, Joseph B. Mandeville2
Massachusetts General Hospital, USA; 2Radiology, Massachusetts General Hospital, Charlestown, MA, USA
    A model of drug self-administration (SA) in non-human primates (NHP) was developed for fMRI to enable longitudinal studies of addiction that assess both the direct effects of cocaine and the neural correlates of drug-seeking behavior. NHP (n=2) were trained to self-administer micro-injections (0.015 mg/kg cocaine) by fixation to a color-coded cue. The timing of the SA paradigm separated 1) responses to drug cues, 2) periods of drug availability, and 3) the direct effects of cocaine. Results showed function inhibition in basal ganglia due to cocaine, and activation of prefrontal cortex associated with cocaine availability.
11:06 795. Effects of Low-Dose Sevoflurane on Regional CBF and BOLD Responses to Auditory Stimulation of Varying Rate and Volume
    Maolin Qiu1, Ramachandran Ramani2, Vivien Rekkas1, Nallakkandi Rajeevan1, Fuyuze S. Tokoglu1, Robert Todd Constable1,3
Diagnostic Radiology, Yale University, New Haven, CT, USA; 2Anesthesiology, Yale University, New Haven, CT, USA; 3Biomedical Engineering, Yale University, New Haven, CT, USA
    Task-induced neuronal activity in the presence of general anesthesia is the result of two counteracting factors: the anesthetic and the task. The former is supposed to suppress neuronal activity in general, while the latter is commonly used in fMRI and usually stimulates focal neuronal activity. It has been demonstrated in a limited number of animal models that the total amount of energy consumed by neurons or the level of neuronal activity in the sensorimotor region must reach the same level regardless of how deep the animal was anesthetized in order to accomplish certain task. However this result has not been observed in humans where the auditory and visual regions were examined in the presence of 0.25 MAC sevoflurane. Among many differences between these experiments, several issues remain to be clarified: e.g., will the strength of the functional stimulus affect the outcome? Will a strong functional stimulus dominates the observed changes in neuronal activity by emphasizing the primary projection against secondary associations? How the level of anesthesia affects the observation? Here we report the results from the study designed and conducted to address these issues.
11:18 796. How Antidepressants Work: SSRI Treatment Induces Adaptive Changes in Brain 5-HT PhMRI Responses
    Darragh Downey1,2, Karen E. Davies1, Shane McKie2, Gabriella Juhasz2, Ian M. Anderson2, Mark A. Smith3, John-Francis William Deakin2, Steve R. Williams1
Imaging Science and Biomedical Engineering, University of Manchester, Manchester, UK; 2Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK; 3 Astra Zeneca R&D, Astra Zeneca U.S., Wilmington, DE, USA
    The delayed therapeutic effect of SSRIs may be mediated by adaptive changes to the 5-HT system following chronic treatment. Desensitisation of the 5-HT system may be observed by BOLD signal changes directly at the site of reuptake inhibition or upstream on integrated networks. Using citalopram challenge phMRI we examined BOLD responses to the acute and chronic effects of citalopram. Significant signal decreases following chronic treatment were found in brain areas implicated in depression and its treatment. We observed adaptive changes to an acute pharmacological challenge suggesting down regulation of receptor expression or enhanced post synaptic signalling following chronic SSRI treatment.
11:30 797. Face Processing and 5-HT: Chronic Citalopram Treatment on BOLD Responses
    Karen Elizabeth Davies1, Darragh Downey1,2, Shane McKie2, Gabriella Juhasz2, Ian Anderson2, Mark A. Smith3, John-Francis William Deakin2, Stephen Ross Williams1
Imaging Science & Biomedical Engineering, University of Manchester, Manchester, UK; 2Neuroscience and Psychiatry Unit, The University of Manchester, Manchester, UK; 3Research & Development, Astra Zeneca, Wilmington, USA
    Serotonin is involved in mood disorders and also emotional face processing. Adaptive changes to 5-HT signalling pathways may result from sustained drug administration and may account for the delayed therapeutic effect of SSRIs. We explored BOLD responses during the processing of faces following chronic citalopram treatment. We observed significant signal reductions in hippocampus, anterior cingulate and prefrontal cortex when observing faces following 11 days of treatment. Citalopram augmented responses in the insula, thalamus and posterior cingulate. These findings suggest that chronic SSRI use modifies 5-HT pathways involved in low level processes which may be involved in treatment response.
11:42 798. Effect of Muscimol on BOLD and Local Neuronal Activity in Awake Animals
    Daniil P. Aksenov1,2, Limin Li1,2, Gheorghe Iordanescu1,2, Xiaomu Song1,2, Alice Wyrwicz1,2
Center for Basic MR Research, NorthShore University HealthSystem, Evanston, IL, USA; 2Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
    Many questions remain about the relationship between the local cellular metabolic and hemodynamic changes measured by fMRI and the underlying neuronal electrical activity. In this study we examined the effect of neuromediators on BOLD and neuronal activity. Simultaneous fMRI and electrophysiological measurements of whisker stimulation were performed before and after localized injection of the GABA agonist muscimol into the somatosensory cortex. The drug injection affected both neuronal activity and BOLD signal. However, surprisingly, the large reduction in single-unit activity produced by muscimol was accompanied by a relatively small change in BOLD response in the whisker barrel cortex.
11:54 799. Double-Blind, Placebo-Controlled, Dose-Response FMRI Trial of Buprenorphine: Differential Valence of BOLD Response Modulation to Innocuous and Noxious Stimuli in Sensory and Striatal Regions
    Jaymin Upadhyay1,2, Julie Anderson1,2, Adam J. Schwarz2,3, Richard Baumgartner2,4, Alexandre Coimbra2,5, Jaime Knudsen1,2, Ed George2,6, James Bishop1,2, Sanjay Keswani2,3, Brigitte Robertson2,7, Rudy Schreiber2,7, David Bleakman2,3, Richard Hargreaves2,8, Lino Becerra1,2, David Borsook1,2
P.A.I.N. Group, Brain Imaging Center, Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA; 2Imaging Consortium for Drug Development, Belmont, MA, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 4Biometrics Research Department, Merck Research Laboratories, Rahway, NJ, USA; 5Imaging Department, Merck Research Laboratories, West Point, PA, USA; 6Department of Anesthesiology and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 7Sepracor Inc., Marlborough, MA, USA; 8Basic Neuroscience Department, Merck Research Laboratories, West Point, PA, USA
    Blood-oxygenation level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) has previously been implemented to observe how specific therapeutics modulate the acute brain (CNS) response to noxious and innocuous stimuli. Buprenorphine (Buprenex) is a mixed opioid partial agonist and antagonist that has been shown to have analgesic and antihyperalgesic effects in humans. In this study, the modulatory effects of two doses of buprenorphine on the CNS response to innocuous and noxious stimulation were investigated with BOLD fMRI.
12:06 800. Regional FMRI Activation in Response to Visceral Stimulation in Rats with Amygdala Implants of Corticosterone
    Jelena Lazovic1, Anthony C. Johnson2, Brent Myers2, Rheal Towner3, Beverly Greenwood-Van Meerveld2
Biology, California Institute of Technology, Pasadena, CA, USA; 2University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 3Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
    Individuals affected with visceral pain often have a history of stressful experiences and anxiety. The aim of this study was to detect brain activation in response to visceral stimulation in the context of increased anxiety, modeled by amygdala targeted corticosterone delivery. FMRI was performed during colorectal distensions (40 and 60 mmHg) in corticosterone or cholesterol (controls) implanted rats. The corticosterone implanted rats had substantially more regions of brain activity for both 40 and 60 mmHg pressure, and greater activation of nuclei involved in pain processing and higher cognitive function (amygdala, hippocampus, entorhinal cortex and cerebellum).
12:18 801. Investigate the Mechanisms of Anesthetic-Induced Unconsciousness in a Mouse Model by High-Resolution Manganese Enhanced MRI (MEMRI) Technique: A Preliminary Study
    Ping Wang1, Jason Moore1, Thomas Floyd1,2, Max Kelz1
Anesthesiology & Critical Care, University of Pennsylvania, Philadelphia, PA, USA; 2Neurology, University of Pennsylvania, Philadelphia, PA, USA
    Manganese is a useful contrast agent for MRI of animals, resulting in enhancement on T1-weighted MRI images. Two emerging hypothalamic targets with proven ability to affect arousal state are the median preoptic nucleus, MnPO, and ventrolateral preoptic nucleus, VLPO. Depolarization of these two regions is respectively thought to underlie onset and maintenance of natural sleep. Our hypothesis is that volatile anesthetics cause unconsciousness (behavioral hypnosis) by affecting VLPO and MnPO function. In this preliminary study, we verified the hypothesis by high-resolution MEMRI (manganese enhanced MRI) technique.