Positron Emission Tomography (PET) to Study Brain Signaling
Condition: Healthy
Study type: Observational

Summary: 
      This study uses positron emission tomography (PET) to examine brain function and signaling
      involving phospholipids, and to see how signaling is related to blood flow. Much of the brain
      is composed of fatty molecules called phospholipids. These molecules are involved in the way
      brain cells signal each other to direct brain function. Brain disease may change
      phospholipids and disturb brain structure and signaling. Studies of brain phospholipid
      composition and metabolism may help clarify how the brain works in healthy people or stops
      working effectively in disease states.

      Healthy volunteers between 18 and 45 years of age may be eligible for this study. Candidates
      are screened with a medical history, physical examination, and blood and urine tests.
      Participants undergo magnetic resonance imaging (MRI) and PET scanning as follows:

      MRI

      MRI uses a magnetic field and radio waves to produce images of body tissues and organs. For
      this procedure, the subject lies on a table that is moved into a metal cylinder (the scanner)
      and wears earplugs to muffle loud knocking and thumping sounds that occur during the scanning
      process. Scanning time varies from 20 minutes to 3 hours, with most scans lasting between 45
      and 90 minutes. Subjects may be asked to lie still for up to 30 minutes at a time.

      PET

      For the PET scan, a catheter (thin plastic tube) is inserted into an artery in the subject's
      wrist or elbow crease to collect blood samples during the procedure, and a second catheter is
      placed in a vein in the opposite arm to inject radioactive tracers. The subject lies on the
      scanner bed, wearing a special facemask and goggles. The mask helps hold the head still
      during the scans, and the goggles either block all light or administer bright flashing
      lights. Radioactive water is injected into the vein, followed by a 1-minute PET scan to
      measure brain blood flow. This is repeated three more times. Then, a radioactive fatty acid
      is injected into the vein, followed by a 1-hour PET scan to measure brain phospholipid
      metabolism. This is repeated once. The images of blood flow and phospholipid metabolism in
      the different regions of the brain under the conditions of darkness and during visual
      stimulation provide information on how and where the brain responds to visual stimulation.
      The entire procedure takes about 3 hours.
    

Detailed description: 
      Objective

      The binding of neurotransmitters and certain drugs to neuroreceptors in the brain is
      considered to modify cognition and behavior by activating certain receptor-coupled effector
      enzymes and initiating signal transduction cascades. One of these effector enzymes is
      phospholipase A2 (PLA2), which when activated will release arachidonic acid (AA) from
      phospholipids and initiate the AA cascade (Fitzpatrick and Soberman, 2001). AA and its
      eicosanoid metabolites have multiple biological actions. We have developed an imaging method
      to quantify and localize brain signal transduction involving PLA2 and AA in unanesthetized
      rats and monkeys, using quantitative autoradiography or positron emission tomography (PET),
      and radiolabeled AA. The aim of this protocol is to extend this method to humans with PET,
      when brain imaging AA signaling in two experimental conditions (dark and visual flash
      stimulation at a frequency of 3 Hz or 8Hz) in the same subject in the same PET session.
      Radioactive [1-11C]AA will be injected intravenously in each condition, and PET will be used
      to measure its incorporation coefficient k* in individual brain regions. Animal studies and
      modeling have shown that the incorporation coefficient is proportion to PLA2 activation and
      the release of AA from brain phospholipids (Rapoport, 2003). In addition, [15O]H20 will be
      injected in each condition to measure regional cerebral blood flow (rCBF). Based on our prior
      studies in human subjects of rCBF during visual activation by flashing lights at different
      frequencies (Mentis et al., 1997; Mentis et al., 1998; Mentis et al., 1996), we hypothesize
      that statistically significant increments in rCBF and [11C]AA incorporation into brain will
      be increased during visual activation compared with the dark (unactivated) condition. These
      increments should be evident in primary visual cortex, association visual cortex, thalamus,
      and frontal cortex. If our hypothesis proves correct and our method to measure [11C]AA
      incorporation both during stimulation and in the dark proves feasible in the same subject in
      the PET session, we believe that the method could be applied generally in humans to examine
      brain PLA2-related signal transduction during physiological or pharmacological activation and
      in healthy aging (Giovacchini et al., In press) and disease, particularly Parkinson and
      Alzheimer disease (Hayakawa et al., 2001; Nariai et al., 1991).

      Study population

      We plan to study 30 normal volunteers, each of whom will be subjected two stimulation
      conditions in the same PET session, visual stimulation at a frequency of 3 or 8 Hz, or a dark
      condition (0 Hz).

      Design

      Each PET scan session will last approximately 3 hours. Each subject will receive a total of
      four [15O]H20 injections to measure regional cerebral blood flow (rCBF), and two [11C]AA
      infusions to measure incorporation k* for AA during a single PET scan session. He/she will
      have an arterial catheter and venous line inserted during the entire session, and one
      transmission scan at the beginning of the session. The order of the scans will be randomized.
      The order of 4 blood flow scans will be: Rest-Photic Activation-Photic Activation-Rest OR
      Photic Activation-Rest-Rest-Photic Activation. The order of two [C11]AA scans will be
      Rest-Photic Stimulation Or Photic Stimulation-Rest.

      Stimulation will be conducted via LED goggles at a flash frequency of 3 Hz and 8 Hz, evenly
      divided among the 30 subjects, and at 0 Hz (dark condition). Statistical parametric mapping
      and other statistical procedures will be used to identify brain regions in which k* for AA
      and/or rCBF is elevated at 3 Hz compared with the dark condition; at 8 Hz compared with the
      dark condition; and at 8 Hz compared with 3 Hz condition.
    

Keywords: Phospholipase A2; Arachidonic Acid; Blood Flow; Coupling; Neurotransmission; PET; Signal Transduction; Activation; Brain; [15O]H20