Decision Making Study in Young and Middle-Aged Adults: Part II
Condition: Healthy Adults
Study type: Interventional
Phase: Phase 1

Summary: 
      Financial decisions are made during pre-retirement age that can influence financial
      well-being for the rest of an individual's life. This proposal aims to construct a more
      comprehensive model of the specific psychological and neural mechanisms that support
      financial decisions in young adulthood and late middle age. In Part 1 of this study (covered
      in Institutional Review Board (IRB) # 141812), middle-age and young adults complete basic
      cognitive, motivational, and decision making tasks and are studied with functional magnetic
      resonance imaging (fMRI) to determine the relation between neural circuit activation and
      individual and age-related differences in decision making. In part II of the study, aspects
      of dopamine functioning are studied using positron emission tomography (PET) scanning to
      determine whether individual differences in dopamine functions are related to the
      decision-making and fMRI measures collected in Part 1 of the study. Dopamine measures include
      baseline D2 receptor availability, amphetamine induced dopamine release and dopamine
      transporter (DAT) levels, which provides a more comprehensive evaluation of dopamine
      functions than in prior studies linking individual differences in dopamine to behavioral,
      cognitive or decision-making traits.
    

Detailed description: 
      The study involves 4 sessions: 1) Informed Consent; 2) Oral d-amphetamine with Fallypride
      PET; 3) Placebo with Fallypride PET; and 4) PE2I PET. The oral amphetamine/placebo conditions
      utilize a double-blind counterbalanced design. The 3 PET sessions will be conducted within a
      6 week window, and whenever possible within a 2 week time period.

      1) Informed consent session: Informed consent will be obtained by Dr. Zald or approved study
      personnel after inclusion and exclusion criteria have been reviewed. Participants are screen
      for inclusion/exclusion as part of a separate IRB protocol (Vanderbilt IRB protocol #141812).
      After the consent processes is completed, participants will also complete the Tests of
      Vigilance and Attention (TOVA: http://www.tovatest.com/), which assesses attention abilities
      and motor impulsivity.

      2 & 3) D-amphetamine/Placebo Fallypride PET Sessions

      Participants complete two [18F]fallypride PET sessions, each lasting approximately 7 hours.
      Scan sessions will all start in the afternoon. Subjects will be instructed to have a moderate
      lunch with no more than a single cup of coffee or tea before coming to the PET center. If the
      scan is not expected to start until after 5 PM, a light snack may also be eaten. After
      determination of blood pressure, respirations, pulse, temperature, an intravenous line will
      be placed in the forearm, the subject will complete ratings of their mood (using the and
      PANAS and the Amphetamine Interview Schedule administered on a laptop computer), and
      participants will have a brief neurological exam conducted by one of the study MDs. An
      initial blood sample for genotyping or estradiol levels (women only) will be acquired.

      The subject will then receive a 0.43 mg/kg oral dose of d-amphetamine or placebo. The
      investigational pharmacy will prepare capsules with 10 mg, and 2.5 mg with dosing rounded to
      the nearest 2.5 mgs (for instance an individual weighing 80 kg would be rounded up to a 35 mg
      dose). The drug dose and placebo, will be placed by the pharmacist in identical containers,
      labeled with the subject's ID and scan day number. A sealed envelope indicating whether the
      dose is d-amphetamine or placebo will be included in case there is a need to break the
      blinding. The study physician, can quickly access this information if there is appearance of
      an adverse drug effect. Otherwise the study physician and experimenters who have contact with
      the participant will remain blind until the participant has completed their second PET scan.
      If a participant has an adverse event that necessitates any medication, or other
      intervention, the blind will be broken to the participant.

      Subjects will have blood pressure and pulse determinations every 30 minutes for the first 2.5
      hours, prior to the start of PET scanning (around 175 minutes post-administration) and every
      60-70 minutes thereafter until the subject's blood is in the normotensive range. In the event
      that the participant's blood pressure exceeds 180 mm Hg systolic, blood pressure will be
      measured every 15 minutes until it shows evidence of reducing (at least a 5 mm Hg decline).
      In the unlikely event that a subject's blood pressure should rise to greater than 200 mm Hg
      systolic B.P. for over 30 minutes, the patient may be treated with intravenous nitroprusside
      at the discretion of the study MD (see risk section below for specific details). We note that
      in our multi-year experience working with oral amphetamine, we have never required such an
      intervention.

      After .5, 1, 1.25, 1.5, 2, 3, hours post-dAMPH/placebo administration and after the first two
      PET scans, approximately 4 and 5 hours subjects will complete ratings of mood (with selected
      items from the Amphetamine Interview Schedule and PANAS) and the DEQ (which asks them to rate
      whether they feel the drug, feel high, like the drug, or want more of the drug). Subjects
      will make their ratings on a laptop computer.

      Cognitive Assessments: To further assess the cognitive specificity of dAMPH effects on
      cognition, participants will complete a battery of cognitive measures under placebo and drug.
      After the 60-minute post-administration blood pressure, mood ratings and blood draw,
      participants will begin performing the cognitive assessments tasks. Testing will include
      measures of speed of processing [WAIS-III Digit Symbol Coding and Symbol Search [115]], a
      measure of the speed of verbal associations [Controlled Oral Word Association Test [116]],
      and a measure of motor speed [finger tapping [151]] and a measure of working memory (2-back
      task). All tasks are included based on literature indicating that these functions are
      modulated by DA (e.g., [124,125]), with the tasks starting immediately following the
      amphetamine. The precise order of these tasks will vary, with brief tasks occurring during
      the 60-75 post-administration period, and the other tasks occurring following the 90 minute
      blood pressure and mood ratings.

      Decision Making and Reward Learning Tasks. A 15-minute behavioral variant of the EEfRT task
      (which requires participants to make decisions about expending effort for rewards) will be
      performed starting 75 minutes after drug administration. In approximately half the trials the
      trial will terminate immediately after the decision phase, skipping both the effort
      expenditure and feedback phase. This approach allows us to complete significantly more
      decision trials during the 15 minute window.

      Participants will also complete a two-stage reward learning paradigm that follows the
      procedures by Daw et al. (2011). On each trial, participants make an initial choice between
      two options labeled by Tibetan characters that lead probabilistically to either of two,
      second-stage "states," represented by different colors (see Figure 2). Each first stage
      choice is associated with one of the second stage states, and leads there 70% of the time. In
      turn, each of the second-stage states demanded another choice between another pair of options
      labeled by Tibetan characters. Each second-stage option was associated with a different
      probability of delivering a monetary reward (versus nothing) when chosen. To encourage
      participants to continue learning throughout the task, the chances of payoff associated with
      the four second-stage options is changed slowly and independently throughout the task,
      according to Gaussian random walks. In each stage participants have 2s to make a choice.
      Inter-stimuli and inter-trial intervals are 500ms and 300ms, respectively, and monetary
      reward is presented for 500ms. The task will take approximately 20 minutes to complete.

      Spontaneous Eye Blinks: During portions of the study procedure participants may be asked to
      wear eye tracking goggles capable of recording spontaneous eye blinks. If participants cannot
      wear the goggles comfortably (primarily due to interactions with prescription glasses), will
      not be asked to wear the goggles.

      Post administration blood draws: 4 blood draws (3 ml each) are taken to measure plasma
      amphetamine levels. These are collected at 30, 60, 90, and 175 minutes post-amphetamine. In
      order to avoid a different blood draw schedule, blood draws will additionally be made on the
      placebo day and will be discarded using appropriate hazardous biospecimen procedures. The lab
      will receive a sealed form that indicates whether to analyze or discard the samples.

      PET scanning and fallypride administration: Scanning will be accomplished with a GE Discovery
      STE PET/CT scanner. 5 mCi of [18F]fallypride (specific activity > 3,000 Ci/mmol) will be
      injected, and subjects will be scanned for 3.5 hours (with two 15 minute breaks) to allow
      estimates of both striatal and extrastriatal binding potential. Dots are placed on the
      subject's forehead and cheeks for periodic visual checks of alignment throughout the scan
      period, and for repositioning after breaks. Three CT scans will also be collected during each
      session for attenuation correction. Blood pressure will be taken during each break and mood
      ratings will be taken during each break. During the second break participants will be given a
      high fat meal to help improve elimination of the radioisotope. Participants will also be
      given fluids to drink and asked to void their bladder.

      At the conclusion of each PET scan on drug and placebo day, vital signs-blood pressure,
      pulse, temperature and respirations - will be measured, a brief motor neurological
      examination performed, and an additional 3.5 ml of blood drawn for a CBC and a comprehensive
      metabolic panel (CMP). If neurological exam and vital signs are normal the participants will
      be released from the study. In the unlikely event that they are not normal, the participant
      will be asked to stay under medical supervision in the VUMC (in one of the rooms in the PET
      center) until these measures have normalized. At the time of release participants will be
      given instructions to drink fluids and void their bladder at least once every two hours for
      up to 6 hours after the time of the start of the PET session.

      4) FE-PE2I PET Session: Participants complete one [18F]FE-PE2I PET session lasting
      approximately 2 hours. Subjects will be instructed to not eat or drink coffee within 2 hours
      of the scheduled appointment. After determination of blood pressure, respirations, pulse,
      temperature, an intravenous line will be placed in the forearm, and a 3.5 ml blood sample for
      CBC and CMP will be drawn.

      5 mCi of [18F]FE-PE2I (specific activity > NLT 457Ci/mmol) will be injected, and subjects
      will be scanned for 1 hour. Dots are placed on the subject's forehead and cheeks for periodic
      visual checks of alignment throughout the scan period. One CT scan will also be collected for
      attenuation correction.

      At the conclusion of the PET scan, vital signs-blood pressure, pulse, temperature and
      respirations will be measured, and an additional 3.5 ml of blood will be drawn for a CBC CMP.
      Participants will be given a high fat snack or meal to help improve elimination of the
      radioisotope. They will also be given fluids to drink and asked to void their bladder.
      Participants will be given a neurological exam, and if both neurological exam and vital signs
      are normal, the participants will be released from the study. In the unlikely event that the
      neurological exam and vital signs are not normal, the participant will be asked to stay under
      medical supervision in the VUMC (in one of the rooms in the PET center) until these measures
      have normalized. At the time of release participants will be given instructions to drink
      fluids and void their bladder at least once every two hours for up to 6 hours after the time
      of the start of the PET session.

      Specific procedures for female subjects of child-bearing potential: Premenopausal without
      hysterectomy or similar procedure, will need to have an additional blood draw within 48 hours
      prior to each PET session to rule out pregnancy (blood drawers will typically be scheduled
      within 36 hours preceding the planned time of radioisotope administration). Women who are
      premenopausal will be only studied within the first 10 days of their menstrual cycle.
    

Intervention name(s): Dextroamphetamine; Placebo; [18F]Fallypride; [18F]-FE-PE2I
Intervention type(s): Drug; Drug; Diagnostic Test; Diagnostic Test
Intervention description(s): One oral dose of dextroamphetamine (0.43mg/kg). The amphetamine is given in order to induce the release of their own dopamine for study with positron emission tomography (PET).; One oral dose of placebo to estimate D2 receptor levels at baseline with PET imaging (necessary to calculate dopamine release in the amphetamine condition).; Radioligand for measuring dopamine D2 receptors with positron emission tomography (PET); Radioligand for measuring dopamine transporters with positron emission tomography (PET)
Other intervention name(s): d-amphetamine; [18F]Fallypride positron emission tomography; [18F]-FE-PE2I positron emission tomography
Intervention MeSH terms: Amphetamine; Dextroamphetamine; Fallypride
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: All subjects receive the same diagnositc intervention, with counterbalanced order
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science