Decision Making Study in Young and Middle-Aged Adults: Part II

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.

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.

Eligibility Criteria:
Inclusion Criteria:

Medically, psychiatrically and neurologically healthy individuals between the 20-30 or 50-65 years of age. Subjects must be able to give informed consent, have an estimated intelligence quotient of greater than 80, and be a fluent English speaker.

Exclusion Criteria:

1. Any condition which would interfere with or be a risk for MRI ( e.g. extreme obesity, claustrophobia, cochlear implant, metal fragments in eyes, cardiac pacemaker, neural stimulator, metallic body inclusions or other metal implanted in the body, facial tattoos with iron pigment). Difficulty lying on one's back and claustrophobia are also exclusions.
2. History of major psychiatric illness (including recurrent major depressive episodes or a depressive episode in the past 10 years, any anxiety disorders in the last 10 years, any history of bipolar disorder or psychotic disorder, a history of substance dependence (or substance abuse lasting more than 2 years), or any eating disorder in which symptoms persisted for more than two years
3. Current tobacco use, alcohol intake greater than 8 ounces of whiskey or equivalent per week, use of any psychotropic medication for the past 6 months (other than occasional use of benzodiazepines for sleep), psychostimulants taken more than 5 times in the subject's life, current marijuana use 4 Neurological illness (other than headache or strictly peripheral nerve disturbance), or head trauma (including more than 2 concussions)

5) Significant untreated or unregulated major medical condition deemed likely to influence cognitive functioning, dopaminergic functioning or neuroimaging measures. Diabetes is an exclusion even if well-controlled.

6) History of Syncope during blood draws 7) Anemia or hematocrit \< 34. 8) Participation in any research studies in the past year that involved radiation, or exposure to radiation on a routine basis due to their occupation.

9) High blood pressure (Systolic B.P. \> 150 in participants under the age of 61, or \> 145 in subjects \> 61 years of age). Diagnosis of labile hypertension. Abnormal EKG indicating potential cardiac risk under conditions of increased blood pressure.

10) Current pregnancy or lactation or plans to become pregnant during the study timeframe.

As part of the screening process in protocol # 141812, participants are initially screened with a brief telephone interview to determine if they meet medical, psychiatric and neurological criteria (all information screened is included in attached screening form). Participants are not consented until after completion of the brief health interview (a waiver of consent is in place in order to perform the initial telephone screening). After being consented participants complete a medical history and physical exam with one of the study MD's. They also complete a psychiatric interview (SCID-IV or V) with one of the trained psychology research assistants or Dr. Zald, and finally an EKG is completed. Participants are not enrolled in the present phase of the study until all exclusion criteria are assessed and they are withdrawn from the study if new information arises that would alter the conclusion regarding any of the inclusion/exclusion criteria after enrollment.