Dopaminergic Neuromodulation of Decision Making in Young and Middle-Aged Adults
Phase: PHASE1
Conditions: Healthy Adults
Sponsor: Vanderbilt University

 
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Neuromodulation of Decision Making in Young and Middle-Aged Adults: Part II    
  
  
David  Zald,  Ph.D.  
Department  of  Psychology  
Vanderbilt  University  
  
Gregory  Samanez-­Larkin,  Ph.D.  
Department  of  Psychology  
Yale  University  
  
Ronald  Cowan,  M.D.  
Department  of  Psychiatry  
Vanderbilt  University  
  
  
  
  
  
  

 
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Over the past century we have witnessed the most rapid increase in life expectancy in human 
history, but for the last several decades the average age of retirement has not increased [18]. 
These biological and cultural trends combined with the current retirement wave of baby boomers 
will continue to put tremendous strain on public programs like Social Security and private 
pension accounts [19]. A common solution raised in public policy debates is to increase the 
retirement age [19]. However, it is not currently clear whether individuals approaching retirement 
age will maintain the motivation to continue working. Vital financial decisions are made during 
this pre-retirement age that can influence financial well-being for the rest of an individual’s life. 
Most individuals in their 60s must determine if they should keep working and continue to save or 
retire and start spending down their savings. However, very little psychological and 
neurobiological research has examined financial decision making in pre-retirement age. As global 
demographics shift, it is vitally important to improve our understanding of the basic mechanisms 
underlying decision making across adulthood [13-15] – from the beginning of working careers in 
young adulthood to the pre-retirement period in late middle age. 
 
Emerging theories suggest that changes in cognition, emotion, motivation, and experience 
across adulthood influence age differences in decision making [20-24]. However, the vast 
majority of empirical studies on decision making across adulthood simply document age 
differences in behavior or choice without investigating the underlying psychological, 
computational, and neural mechanisms. To move forward, a more mechanistic account is 
necessary [25]. An overarching goal of this grant is to begin to construct a more comprehensive 
model of the specific psychological and neural mechanisms that support financial decisions in 
young adulthood and late middle age. Our integrative approach includes measurement of 
cognitive and affective individual differences, decision-making behavior, functional and structural 
brain imaging, and pharmacological manipulations of neural systems. This work is primarily 
focused on effort-based decision making, but we will also examine sensitivity to reward 
magnitude and probability. 
 
In our attempts to maximize wellbeing, the decisions we make require the integration of a 
number of features. For example, nearly all decisions require the weighing of expected benefits 
with any associated costs, which involves taking into account factors such as the exertion of effort 
required to achieve various outcomes or the probability of the outcome of a choice [26-28]. 
Depending on an individual’s preferences, these features may systematically diminish the 
subjective value of decision outcomes (Fig. 1). Importantly, 
preferences may change across adulthood and differentially 
influence decisions. As reviewed below, recent studies have 
begun to examine changes in preferences with age and associated 
neural function, but there are large gaps and a number of 
methodological limitations of the existing literature.  
Effort. In animal research, effort-based decision-making 
paradigms have been widely used to study motivation [29] and 
the tolerance for physical costs in order to obtain a goal [30,31]. 
These paradigms involve repeated choices in which an animal 
must choose between a freely available, but smaller or less 
palatable food reward (Low-Cost/Low-Reward, LC/LR), as 
compared to a larger or preferred food reward, for which the 
animal must expend effort to obtain (High-Cost/High-Reward, 
FFigure 1. Decision features 
such as effort demands and 
probability may decrease 
the subjective value of a 
fixed amount of reward. 

 
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HC/HR). Effort expenditure in these paradigms has included scaling a barrier or engaging in 
repeated lever-pressing. Healthy animals show an overwhelming preference for HC/HR options, 
while various forms of interference with corticostriatal brain systems result in a shift towards 
more LC/LR choices. Forms of interference that result in a preference for LC/LR options include 
6-OHDA lesions of nucleus accumbens (NAcc) dopamine (DA) terminals, blockade of NAcc DA 
D2 receptors, lesions of the anterior cingulate (ACC), DA D1-receptor blockade in the ACC, 
suppression of excitatory signaling from amygdala to ACC [32], or disruption of excitatory 
signaling from ACC to NAcc [33]. 
 
In order to assess effort-based decision making in humans, we developed the Effort 
Expenditure for Rewards Task (EEfRT or “effort”), which has been carefully modeled after 
effort-based paradigms developed by Salamone and colleagues [34]. Briefly, subjects perform 
repeated trials in which they choose between expending more effort (in the form of speeded 
manual button presses) to achieve a greater monetary reward (HC/HR), or less effort for a smaller 
reward (LC/LR). Individual trials vary in terms of the reward magnitude offered for the HC/HR 
option, as well as the probability of receiving a monetary reward for a given trial. This task has 
been previously shown to be sensitive to individual differences in trait anhedonia, such that 
individuals reporting greater anhedonic traits on the Chapman anhedonia scale [35] or the Beck 
Depression Inventory anhedonia scale made fewer HC/HR choices [16]. Studies in psychiatric 
populations are ongoing, but have strongly indicated changes in the context of affective disorders. 
Importantly, the EEfRT provides a means of assessing not only whether individuals choose 
HC/HR options, but also the subject’s sensitivity to variables that influence these decisions, such 
as reward magnitude and reward probability. As in animal studies, EEfRT performance is 
modulated by manipulations of the DA system. Critically, we have demonstrated that release of 
DA induced by administration of d-amphetamine (dAMPH) dose-dependently increases the 
proportion of HC/HR choices [17]. Further, we have demonstrated in young subjects that EEfRT 
performance is related to measured DA functioning [36]. 
 
Despite the ubiquity of effort-based decisions, and increasing attention to effort-based 
decision making in studies and theories of psychopathology [37], there are currently no published 
studies of preferences for effort in middle-aged or older adults. Yet, effort is a rapidly growing 
area of interest in both clinical psychology [16,37] and decision neuroscience [17,29,38]. 
Stereotypes of pre-retirement age as a time of shifting preferences toward physical relaxation and 
leisure might suggest that tolerance of physical effort declines across adulthood. Although there is 
not yet any available empirical evidence related to effort and decision making in late middle age, 
age-related declines in DA may contribute to a lower tolerance for effort [26]. This lowered 
tolerance may be further exacerbated by an increase in physical motor limitations and ease of 
muscle fatigue with age [39], although these peripheral effects are likely more influential later in 
old age. Together this leads us to predict a reduced tolerance for physical effort in late middle age. 
We also expect middle-aged adults to show a larger difference in neural activation in mesolimbic 
DA target areas for higher relative to lower effort choices during fMRI of an effort-based decision 
task. 
Probability. The impact of dAMPH on the EEfRT is notable in that its strongest impact is on the 
low probability trials, when there is a significant chance of not obtaining a reward [17]. Despite 
popular stereotypes of older adults being more risk averse than young adults in the face of 
uncertainty, a quantitative meta-analysis conducted by a member of our research team reveals that 
behavioral risk preferences (tolerance of low probabilities) do not globally differ between younger 
and older adults [40]. Although different patterns of risk taking or risk aversion emerge for certain 

 
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classes of decisions [40], these differences appear to be more related to cognitive limitations than 
true preferences. Such findings suggest the possibility of dissociations between changes in effort 
and probability discounting. However, there are currently no existing studies that have examined 
relationships between effort and probability preferences in young and middle-aged adults.  
 
Subjective Valuation and Neural Systems 
The work reviewed thus far has focused on how features of decision options (tolerance for effort 
and probability) may influence choice differentially across adulthood. Importantly, age and 
individual differences in goals and preferences directly influence the subjective value of a 
decision option. For some decisions, it is possible to compute a mathematical expected value 
(independent of an individual’s preferences), in dollars, for each choice. In contrast, the subjective 
value of an option is just that, subjective. The value or utility of an option to a given individual is 
dependent on their preferences. Observable decisions reflect these subjective values people hold 
about the outcomes. This concept of subjective valuation has been a strong focus of recent 
decision neuroscience research. 
 
Neuroimaging work suggests that there is a unitary neural system supporting subjective 
valuation [41-43]. This work is just beginning to focus on effort cost integration [44], with more 
work examining related decision costs such as uncertainty and temporal delays [41-43] in healthy 
young adults. The medial prefrontal cortex and ventral striatum lie at the core of this system. 
Preferences for risk and ambiguity are reflected in a shared mesolimbic subjective valuation 
system [43]. There is also some evidence for domain generality such that a shared aspect of this 
core subjective valuation system underlies risky decisions about both primary rewards (food, 
water) and money [41]. Such data raise the possibility that influences on subjective valuation may 
provide a pervasive impact on decision making regardless of the type of cost. With one recent 
exception [45] regarding uncertainty, this prior neuroimaging work has exclusively used fMRI, 
which cannot fully address the specific neurochemical modulation of these signals. However, 
these regions of the striatum and medial prefrontal cortex are primary targets of ascending 
midbrain DA projections. Thus, it has been argued that subjective valuation is dependent on these 
more ventromedial aspects of the DA system. 
 
In Part I of this study we are examining behavioral and neural sensitivity to monetary 
reward and physical effort costs in young adulthood and late middle age. In a sample of healthy 
young (ages 20–30) and late middle-aged (ages 50–60) adults, we are using functional MRI to 
examine basic aspects of reward processing using the Monetary Incentive Delay (MID) task and 
sensitivity to effort costs using the Effort Expenditures for Reward Task (EEfRT). Participants in 
Part 1 of the study are also screened for eligibility for Part II of the study.  
 
In the present (Part II) portion of the study, we will use positron emission tomography 
(PET) imaging to determine whether individual differences in DA functions are related to the 
decision-making and fMRI measures collected in Part 1 of the study.  DA imaging will include 
striatal and extrastriatal baseline D2 receptor availability, amphetamine-induced DA release (a 
marker of DA system responsivity) and DA transporter levels. This approach provides a more 
comprehensive evaluation of DA functions than in prior studies attempting to link individual 
differences in dopamine to behavioral, cognitive or decision-making functions.  In addition to 
allowing us to test key hypotheses about DA and behavior, this study will also allow us to address 
several questions about age-related and individual differences in DA functions, including 1) 
whether age related declines in striatal and extrastriatal D2 receptor levels covary with changes in 
DAT, 2) whether there are age related changes in DA system reactivity to amphetamine, and 3) 

 
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whether individual differences in baseline levels of DAT uptake are associated with the amount of 
amphetamine-induced DA release (which is predicted given that DAT is the target site for 
amphetamine, but has never been tested in humans. Additionally, we will be able to examine 
whether baseline differences in DAT are related to the behavioral effects of amphetamine  
 
2.0 Specific Aims:  
There are three specific aims of this phase of the study 
Aim 1: To test the hypothesis that multiple aspects of mesolimbic DA function are uniquely 
associated with age differences in decision behavior. 
Based on preliminary data, we expect to observe larger age differences in DA D2-like receptor 
availability in the pallidum and frontal cortical regions, but smaller (but measurable) declines in 
the ventral striatum. We hypothesize that middle-aged adults will show significantly lower levels 
of DA release in the striatum and medial prefrontal cortex and DAT expression in the striatum 
compared to younger adults. Across both groups, we expect individuals with greater DA release 
in the ventral striatum and ventromedial prefrontal cortex to be more tolerant of effort costs.  
 
Aim 2:  To examine the influence of individual and age-related differences in DAT on dAMPH-
induced DA release.  Given that DAT is the primary site on which dAMPH acts, we will test the 
hypothesis that individual differences in DAT expression substantially predict DA release and the 
subjective effects of dAMPH.  Because DAT declines with age, we additionally hypothesize that 
dAMPH-induced DA release will be lower in the middle aged than the young adult sample. We 
additionally predict that the combination of DA midbrain autoreceptor levels and striatal DAT 
levels will predict dAMPH induced DA release better than either index in isolation. 
 
Aim 3: To examine the influence of dAMPH-induced DA release on cost-benefit decision making 
in young adulthood and late middle age. 
 
We recently demonstrated that dAMPH increases tolerance of physical effort costs in healthy 
young adults. Young and middle-aged adults will complete a behavioral version of the effort-
based task in two sessions (placebo, dAMPH).  We expect that tolerance of physical effort will be 
increased under dAMPH in both age groups, with differences in the extent of modulation 
correlating with measures of baseline DA functioning and DA release. 
  
3.0  Recruitment  and  Inclusion/Exclusion  Criteria  
3.1 Recruitment: Subjects are recruited directly as part of IRB#141812 Neuromodulation of 
Decision Making in Young and Middle-Aged Adults Part I.  No recruitment external to that study 
are planned.  Participants in IRB#141812 are recruited through online advertisements including 
the Dept. of Psychology Paid Subject Pool (Sona Systems), ResearchMatch and Craigslist, and 
fliers posted around the Vanderbilt campus or in local community organizations or handed out at 
health related events). 
3.2.  Criteria for inclusion and exclusion and procedures used to determine eligibility: 
 
    Inclusion:     a) Be between the ages of 20-30 or 50-65 
 
             b) Be able to give informed consent 
              
             c) Have an estimated intelligence quotient of greater than 80 
 
 
 
 d) Fluent English speaker 

 
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  Exclusion:    a)  History of substance dependence (or prolonged substance abuse lasting 
more than 2 years) or positive urine drug screen 
 b) Use of any psychostimulants (other than caffeine) in the last 6 months 
or more than 4 times in lifetime 
 c)  Current tobacco (or nicotine use), or alcohol intake greater than 8 
ounces of whiskey or equivalent per week 
 d) Any psychotropic medication for the past 6 months other than 
benzodiazepines for sleep 
 e)  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 
dysthymia, any psychotic disorder, or any eating disorder in which 
symptoms persisted for more than two years) 
 f)  History of neurological disorder (excluding headaches or problems 
limited to peripheral nerves), or history of head trauma (other than a 
single concussion) 
 g)  Significant untreated or unregulated major medical condition deemed 
likely to influence cognitive functioning, dopaminergic functioning or 
neuroimaging measures  
 h) Any condition which would interfere with MRI or PET studies, e.g. 
extreme obesity, claustrophobia, cochlear implant, metal fragments in 
eyes, cardiac pacemaker, neural stimulator, tattoos with iron pigment 
and metallic body inclusions or other metal implanted in the body 
which may interfere with MRI scanning. 
i)   Pregnancy, lactation or trying to get pregnant during the month during 
which the study is to take place 
  
j)   Anemia, a hematocrit below 34 
 
k)   Diabetes, hypoglycemia, or any condition that could would prevent the 
participant from fasting for 6 hours  
l)   Recent participation in studies involving radiation or routine 
occupational exposure to radiation. 
m) High blood pressure (Systolic B.P. > 150), or an abnormal EKG 
indicating potential cardiac risk under conditions of increased blood 
pressure. If subject is over 60, baseline B.P. > 145.  
 
Inclusion/Exclusion criteria are determined based on data obtained during IRB#141812 (with the 
exception of the plasma pregnancy exam for women of child-bearing potential which is collected 
within 48 hours prior to each PET scan. At any point in the study, the study PI (Zald), or one of 
the study physicians may withdraw a participant if they find new evidence that the participant has 
an exclusionary condition.    
 
Up to 70 subjects may be consented for the study, with the aim of having 60 subjects total 
complete the PET studies.  No more than 60 subjects (30 per age group, with equal gender 
representation).  No subjects will be consented after the 60th participant is scheduled for a PET 
scan unless we have another withdrawal from the study.    
  

 
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4.0  Study  Procedures  
4.1 Primary Study Procedures: The study involves 4 sessions:  Informed Consent, Fallypride PET 
+ placebo, Fallypride PET + oral d-amphetamine, and PE2I PET.  The 3 PET sessions will be 
conducted within a 6 week window, and whenever possible within a 2 week time period.  
 
4.2.  Informed consent session: Informed consent will be obtained by Dr. Zald or approved study 
personnel after inclusion and exclusion criteria have been reviewed. This will be done in the Dept. 
of Psychology at Vanderbilt University.  Written consent materials are provided to the participant 
originally when they complete the related IRB protocol #141812.  Although given to participants 
during Part I of the study, Participants only sign the consent for the 2nd part of the study after 
completing the prior study and passing inclusion and exclusion criteria assessed during that study.   
 
In the present study, participants are given time to read (or reread) the written informed 
consent document in a quiet private room. They are asked if they have any questions about the 
protocol. If they have no questions or the researcher has any concerns about whether they 
understand the procedures, the researcher will briefly review the steps of the study.  Because the 
participants will have already completed IRB #141812, the researchers will already have some 
knowledge of the participants level of cognitive functioning, and if there is a concern about the 
participants ability to understand the procedures based on their past performance on cognitive 
measures they will be excluded from the study.  
 
After the potential participant indicates they have read the document, Dr. Zald or his 
associate will briefly review specific procedures and their risks (especially those related to 
administration of amphetamine and PET radioisotopes), and the subject will be given a chance to 
ask questions. The participants will only be asked to sign the informed consent document after 
any and all questions have been answered.  
 
After signing the informed consent, participants will receive a brief training on how to 
perform the two-stage task (this will help reduce the amount of time needed for training on that 
task on the fallypride PET scan days).  Participants will also complete the Tests of Vigilance and 
Attention (TOVA: http://www.tovatest.com/), which assesses attention abilities and motor 
impulsivity. 
 
4.3 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.  
 
4.4 Fallypride PET Sessions (with placebo or oral d-amphetamine). 
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. 

 
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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 oral clonidine 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 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.  
 
4.41 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.   
 
4.42: 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 

 
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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.   
 
Participants keep any money won during the two decision-making tasks, which we 
estimate will be around $40 between the two tasks (range = $20-60).  
 
 
 
 
 
4.43 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.  
 
4.44 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.  
 
4.45 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 

 
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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.  
 
4.5 FE-PE2I PET Session  
All participants complete one [18F]FE-PE2I PET session lasting approximately 2 hours. Female 
subjects capable of childbearing will have a plasma beta HCG determination within 48 hours of 
the PET study.  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.  
Scanning will be accomplished with a GE Discovery STE PET/CT scanner. 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. 
Participants may be asked to complete an extended [18F]FE-PE2I scan in order to establish 
radiation-dosimetry. Our current estimates of [18F]FE-PE2I uptake are based on nonhuman 
primate data. A small number of subjects will complete an extra hour of scanning, with no 
additional injection.  For the extra PET scanning the scanner will be switched into whole body 
mode so as to scan the critical organs of the torso, including gonads).  Participants will be 
exposed to one extra CT scan (covering the torso/gonads), and will have up to 14.5 additional 
blood drawn to measure the metabolites of [18F]FE-PE2I. 

 
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5.0 Risks 
Possible risks from the study include administration of radiopharmaceuticals and oral d-
amphetamine, venipuncture, and the discomforts associated with PET scanning 
  
Radiopharmaceuticals: Subjects are exposed to radiation from the two [18F]fallypride scans 
and, the single [18F]FE-PE2I scan, and the CT scans that are used for attenuation correction.   The 
total radiation dose associated with one PET study is approximately 1900 mrem. This dose 
corresponds to the background radiation received in 6 years from the environment. Dosing at this 
level is within FDA guidelines, and large-scale studies of the long-term risk of radiation exposure 
(within FDA limits) have shown no increase in rates of cancer associated with this amount of 
exposure.  
In addition, there is a potential adverse response to the injections themselves.  This risk is 
minimal because [18F]fallypride and [18F]FE-PE2I are injected at subpharmaceutical (tracer-level) 
doses, and procedures are in place to ensure quality control in terms of requirements for high 
specific activity, chemical purity and demonstrated sterility. Dr. Zald and colleagues have now 
performed over 200 [18F]fallypride PET studies at Vanderbilt and have seen no laboratory 
abnormalities from administration of this radiopharmaceutical. The only adverse event seen in 
these studies was a single subject who became nauseous, but review of the case suggested that 
this may have related from hypoglycemia due to fasting before the study.  
We lack past experience with injecting [18F]FE-PE2I at Vanderbilt, but no reports of adverse 
events have been reported at other institutions using the radioligand, and qualifying runs have 
shown suitable specific activity, chemical purity and sterility.  A nuclear medicine physician will 
be available within the Department of Radiology in case a problem arises that requires attention. 
 
Administration of Amphetamine: The primary risks associated with the use of dAMPH include 
an increase in blood pressure, psychological effects (i.e. feeling jittery, anxiety, increased 
alertness and restlessness), and difficulty sleeping. Numerous studies of oral dAMPH in normal 
volunteers have been reported. A 0.5 mg/kg oral dose of dAMPH produced a mean elevation of 
28 mm Hg increase in systolic blood pressure at 2 hours, i.e. a peak systolic blood pressure of 148 
which decreased to a 14 mm Hg increase at 4 hours and returned to normal levels by 6 hours. The 
pulse rate remained unchanged [145,176]. Our own data in young adults exposed to our standard 
dose of 0.43 mg/kg indicates a mean increase of approximately 27 mm HG at peak (148 mm Hg) 
that occurs by 3 hours, and decreases substantially by completion of scanning. Based on these 
data we anticipate that a 0.43 mg/kg dose of dAMPH should produce blood pressure elevations of 
25-30 mm Hg on average. To limit risk, we apply strict blood pressure restrictions on enrollment 
(systolic no more than 150 mm Hg).  The average systolic blood pressure is 120 (average range: 
108-133) for the age range 20-30, and 130 (average range: 116-144) for the age range 50-60.  
With an inclusion cutoff of 150 mm Hg, we do not anticipate many participants exceeding 180 
mm Hg on dAMPH.  This is within the normal range for systolic blood pressure for exercise (160 
- 220 mm Hg). Participants with a reported history of labile hypertension will also be excluded, 
since they would be at increased risk for a blood pressure elevation. Participants will also be 
given an EKG and will be excluded if there are any abnormalities that would represent a risk 
under a condition of temporary elevation of blood pressure.  Participants' blood pressure will be 
monitored by medical staff during their time in the study (every half hour), and standard of care 
intervention will be administered if there is a sustained elevation in blood pressure > 200 mm Hg 

 
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for more than 30 minutes. The default treatment strategy for sustained high blood pressure will be 
administration of 0.3 mg oral clonidine, which typically begins lowering blood pressure within 30 
minutes.  We note that in the unlikely event that the study physician felt a more rapid lowering of 
blood pressure was essential for patient safety, the study MD could select administration of 
intravenous nitroprusside as part of a standard of care treatment for a blood pressure emergency, 
but we do not anticipate any situations in which this should necessary. We note it in the protocol 
only for purposes of thoroughness – and any case where this would be necessary would warrant 
an adverse event report to the IRB. In all of our past studies intervention has never been necessary 
following amphetamine (although we note that the majority of subjects studied in our lab to date 
were under 40 years of age). A study medical doctor (Dr. Cowan or his surrogate) will be in the 
PET suite or the medical campus throughout all procedures and will be notified immediately if 
blood pressure exceeds 170 mm Hg systolic on any reading.  
       Psychological effects range from positive effects to some mild negative subjective 
emotional states including feeling jittery, anxious or restless. These negative emotional states 
resolve within a few hours of drug administration and are consistently gone by the time subject's 
leave the study. Participants are given a number to reach the investigators if they are experiencing 
any acute negative emotional events in the hours after they leave the study, although we have 
never had a participant feel the need to contact us following exposure to amphetamine.  
Participants may have difficulty falling asleep in the evening after amphetamine administration. 
They are advised of this, and told: 1) not to make any major decisions or drive following the 
study, and 2) not to schedule anything too early in the morning the next day.  The study staff will 
make transportation arrangements in cases where someone does not have a ride option after the 
scans.  We additionally try to start drug administration by 2 PM in the afternoon, so that 8-hours 
have passed by a typical bedtime.  
 
There is a potential ethical concern regarding the administration of psychostimulant drugs 
to healthy non-drug using normal control subjects. We have relied on guidelines developed by the 
National Advisory Council on Drug Abuse (NACDA; appointed by the Secretary of Health and 
Human Services and Advisory to the National Institute of Drug Abuse). The entire report is 
available at: http://www.nida.nih.gov/funding/hsguide.html. In addition, we have relied on the 
"Human Subject Issues in Drug Abuse Research" published by the College on Problems of Drug 
Dependence (Adler, 1994) which states "There is no evidence that exposure to drugs in a research 
setting enhances the desire of an individual to use drugs, leads the individual to addiction, 
worsens the addiction of an individual, or makes an addict more difficult to treat".  For the sake of 
thoroughness, we have provided pertinent excerpts from the most recent NACDA guidelines as a 
supplement to this application. 
 
Venipuncture: There is a risk of local bruising and discomfort associated with venipuncture for 
obtaining blood samples and placement of IV lines for the PET studies. A small amount of 
bleeding may occur when an IV line is inserted or removed. While there is the possibility of 
infection associated with venipuncture, this is very unlikely. Participants with anemia are 
excluded in order to avoid problems associated with repeated blood draws. 
 
   Discomfort associated with PET scanning: Participants may experience some discomfort due to 
having to remain motionless for up to 70 minutes at a time during PET scanning.  Participants are 
given pillows to help them get comfortable before the start of the scans.  
 

 
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5.1  Reporting  of  Adverse  Events  or  Unanticipated  Problems  involving  Risk  to  Participants  or  
Others 
  
Each study will be monitored by Dr. Cowan or one of the approved study M.D.’s in his absence. 
The physician will monitor vital signs, physical and mental status, in real-time, to assess for 
adverse events and safety concerns. Subjects will be discharged with instructions to call 
immediately for any concerning signs or symptoms. Adverse events will be classified mild, 
moderate or severe as follows: 
  
1)  
Mild – Adverse effects including events which do not produce functional 
impairment and do not require intervention or promptly respond to treatment.  
 
2)  
Moderate – Moderate side effects include events and pharmacological effects 
which may affect function and pharmacological effects of drugs which do not 
respond promptly to treatment but are reversible over a period of hours. 
 
3)  
Severe - Adverse effects are those which are life-threatening, incapacitate the 
subject, and in the case of pharmacological effects do not respond to treatment 
and do not resolve within hours. 
 
Adverse events or unanticipated events will be attributed to the study as follows: 
 
1)   Probable: The adverse event is likely related to the study. 
 
2)   Possible: The adverse event occurs within 96 hours of the end of the study, but 
may be related to other factors. 
 
3)   Unrelated: The event occurs more than 96 hours after the end of the study and 
is more likely due to extraneous factors. Probable or possible serious adverse 
events will be reported to the IRB within 10 days. 
 
All potentially serious adverse events will be reviewed on a real time basis. All adverse 
events will be reviewed with Dr. Warren Taylor during regular review meetings. Any 
adverse events that could be deemed moderate or greater, and probable or possible, will 
lead to a meeting with Dr. Taylor at his earliest possible schedule opening (within 48 
hours of the event). All events that either the PI or Dr. Taylor consider to be severe 
adverse events, which are probably or possibly related to the study will be reported within 
7 days to the IRB, and within 10 days to the FDA by Dr. Zald (and Jeffrey Clanton, MD, 
who is the physician in charge of the institutional IND), and NIA program officer by (Dr. 
Zald). Additionally, any unanticipated event that is considered moderate and possibly or 
probably related to the protocol will be reported to the IRB (but not the FDA or NIDA 
program officer) within 10 days. Annual reports of all adverse events (regardless of 
severity) will be made to the IRB (by Dr. Zald) and FDA (by Dr. Zald and Clanton). Note, 
non-pharmacological adverse events, such as vasovagal responses to the placement of the 
IV line, will not be included as part of FDA reporting as they are unrelated to the 
investigational drug.  

 
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Data and Safety Monitoring 
The PI will meet with the data safety monitor on an annual basis to review participant data. Data 
to be reviewed will include any descriptions of impaired functioning reported by the medical staff 
involved in the project including pre- and post-administration neurological exam, pre- and post-
administration vital sign, CBC and CMP. Any unanticipated adverse events will be reviewed with 
the data safety monitor within 48 hours of the event in order to evaluate the event, determine 
reporting requirements, and evaluate if protocol changes are necessary.  
  
6.0  Study  Withdrawal/Discontinuation  
  
Subjects may elect to withdraw from the study at any point. The investigator may discontinue an 
individual’s participation in the study for the following reasons: 
 
1)   The participant becomes pregnant. 
 
2)   The subject is found during screening to have laboratory results,  
      physical findings, or psychiatric history that are exclusion criteria. 
 
3)   The subject has an adverse events of moderate severity or greater who, in the judgment 
of the principle investigator, may be unable to complete the study or whose health may 
be compromised by further participation.  If an adverse event occurs, immediate 
treatment will be provided.  
 
4)   A subject cannot complete the study in a reasonable period of time, i.e. >3 months. 
Subjects will be informed of this possibility orally and then in writing prior to 
discontinuation. 
 
If a subject is discontinued by the investigator during the initial session of the study or 
because of a failed drug screen, they will not be reimbursed for their time. If they are discontinued 
because of medical or psychiatric reasons, they will be compensated at a rate of $10 per hour 
spent in the study up to a total of $150. If the study was discontinued after administration of 
[18F]fallypride, the subjects will be paid for the complete study. 
  
  
7.0  Statistical  Analysis  Plan  
  
Aim 1 tests the hypothesis that aspects of mesolimbic DA function are associated with age 
differences in decision behavior. 
PET Analyses. A region of interest (ROI) approach will be used in the first set of analyses to 
examine age group differences in D2 binding (placebo BPND), DA release (DBPND), and DAT 
uptake in a set of eight brain areas. We will define subcortical (e.g., caudate, putamen, globus 
pallidus, thalamus) ROIs based on adapted methods developed for adults of various ages [173] by 
consultant William Jagust. We will define a lateral cortical ROI based on the results of a PCA (as 
in [153])  We will also anatomically define smaller key regions of interest in the midbrain 
(VTA/SN), ventral striatum (nucleus accumbens), and ventromedial prefrontal cortex using 
previously published guidelines [110,111] within individual subjects. For initial analyses all ROIs 

 
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will be averaged bilaterally, but follow-up tests will also be conducted to determine whether any 
ROIs warrant bilateral specification. D2 BPND (placebo) will be extracted for all eight ROIs, 
while DA release (DBPND ) and DAT expression will be extracted from ROIs restricted to only 
those where there is substantial signal to noise (e.g., VTA/SN and striatal sites for DAT).   
We will first test for expected age related differences in DA variables, using ANOVAs with 
Age group as the independent between subjects variable of interest.  Separate analyses will be 
performed for BPND,  DBPND) , and DAT measures.  We will also test for interactions between age 
group and region to test the hypothesis that there will be larger age differences in DA D2-like 
receptor availability in the pallidum and frontal cortical regions, but smaller (but measurable) 
declines in the ventral striatum. We expect that middle-aged adults will show significantly lower 
levels of DA release in the striatum and medial prefrontal cortex and DAT expression in the 
striatum compared to younger adults.  
We will next test the whether the dopaminergic measures predict behavioral differences in 
decision making. Across both groups, we expect individuals with greater DA release in the 
ventral striatum and ventromedial prefrontal cortex to be more tolerant of effort costs.  
 
Aim 2 examines the hypothesis that individual and age-related differences in DAT are associated 
with dAMPH-induced DA release.  This will be studied using striatal ROIs and ANOVA with age 
group serving as a between subjects variable.   
 
Aim 3: To examine the influence of dAMPH-induced DA release on cost-benefit decision making 
in young adulthood and late middle age. We expect that tolerance of physical effort will be 
increased under dAMPH in both age groups, with differences in the extent of modulation 
correlating with measures of baseline DAT functioning and DA release. This will be 
accomplished by ANOVA analysis with age group as a between subjects variable.  
 
Mediation Analyses: In each of the above cases we will utilize a mediation analysis to test 
whether expected age differences in behavior (effort performance, responsivity to d-AMPH) are 
mediated by age related differences in regional DA functions.  
 
Exploratory voxel-wise analyses: Beyond the ROI analyses, more exploratory whole-brain 
voxelwise analyses will be conducted. For these analyses, individual difference measures (e.g., 
choice preferences, trait affect, cognitive ability, etc) and age will be mean-deviated and entered 
as regressors of interest to predict BPND. The resulting whole-brain maps will be thresholded at 
whole brain pcluster-corrected < 0.05. 
 
Relative Influence of Different DA Measures. By assessing multiple aspects of the DA system it 
will be possible to assess the relative influence of different aspects of the DA system on 
behavioral measures. We will first use a PCA analysis of ROI data for cortical and subcortical 
ROIs for binding potential, striatal and ventromedial prefrontal DA release, and striatal and 
midbrain DAT. We expect there to be a positive correlation between all of these variables, 
reflecting an overall integrity of the DA system, but for separate components to arise reflecting 
region and measure specific variance [153]. We will then assess the relative impact of the DA 
variables, by utilizing step-wise regression to determine which variables provide the strongest 
influence on the behavioral variable, and whether, as predicted, a combination of DA measures 
provides significantly greater explanation of the behavioral variable than the measures taken in 
isolation. Further, we expect the inclusion of each additional measure of DA function to reduce 
the significance of the age effect on differences in sensitivity to effort costs. We expect that a 
model that includes D2 receptors, DA release, and DAT expression will reduce the age effect to 

 
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non-significance, indicating that the age effects are mediated by the DA variables. We will also 
formally test a mediation model. 
 
Control for Morphometry: When imaging the aging brain it is extremely important to address 
age differences in morphometry. Aside from common issues that arise with BOLD fMRI [108], 
findings from prior PET studies of aging may be limited by a lack of control for morphometric 
changes with age. Lacking information on morphometry, it is possible that observed declines in 
striatal D2 BPND could be partially due to changes in grey matter rather than a specific D2 deficit. 
An additional innovation of this project is that we will examine the role of morphometric change, 
by directly examining whether controlling for grey matter volume changes the results, applying 
partial volume averaging corrections for ROI analyses, and voxelwise procedures based on 
voxelwise morphometry techniques (see [154,174] for method details and feasibility).  
 
Statistical Power: The analyses of age differences will be conducted with age as a 
dichotomous variable. The group difference effects that have been observed in relevant recent 
studies of decision making or corticostriatal brain activity [109-112] range from around d=0.75–
1.5. To detect the lower extent of these effects, a total sample size of at least 60 (30 per group) is 
recommended for a power of .80 at p < .05 two-tailed. Across the sample and within age groups, 
we will examine relationships between continuous measures (e.g., task performance, cognitive 
ability, emotional traits, fMRI neural activity, PET DA measures). The individual difference 
correlations that have been observed in related studies range on average from r=0.3–0.6. To 
detect an average correlation of r=.5 within each age group (with up to two other covariates in 
the model), a sample size of at least 32 is recommended for a power of .80 at p < .05 two-tailed. 
Individual difference analyses that combine the age groups (N=64) will provide a power of over 
.95 to detect a correlation of r = .50 at p < .05 two-tailed (allowing for up to three covariates in the 
model). An r of this level is consistent with our past level of correlations between individual 
difference measures and DA BPND within healthy young samples [78,79]. We will also require this 
sample size to have sufficient power to detect interaction effects (see later hypotheses on age 
differences in DA measures). 
 
  
8.0  Privacy/Confidentiality  Issues  
  
All subject information is kept in a locked file cabinet in the offices of PI and/or co-investigator. 
Image data are only accessible to study personnel on password-protected computers. Wherever 
possible, data is stored as a study ID number instead of with the subjects name in order to limit 
subject identification. This includes all genetic information, financial and credit report data, and 
drug screening data. Subjects are warned in advance and consent to the fact that oversight 
agencies (FDA, local IRB, etc.) may request and receive access to portions of their data. A 
certificate of confidentiality will be obtained from NIH prior to the start of the study in order to 
specifically protect participants from any forced disclosure of information related to past or 
present drug usage, psychiatric status, or genotyping information. All individuals who will come 
in contact with the patients or their data as part of this study are required to first pass a test on 
research with human subjects (approved by the Vanderbilt University Institutional Review Board) 
in order to ensure they understand the importance of confidentiality issues. 
  
9.0  Follow-­up  and  Record  Retention  
  
The initial study is estimated to last 3–5 years. If funding is obtained for longitudinal extension 
studies after the initial study period, the study could last longer (5+ years). All records and data 

 
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will be retained in locked cabinets and archived indefinitely following completion of the study. 
After 10 years, records that are not needed for FDA reporting may be discarded (shredded).  
 
Participants may be recontacted after completion of the study in order to request they complete 
additional personality measures, and to measure their weight (based on evidence that dopamine 
functioning impacts body mass index). No other follow-up is planned. Participants may opt-out of 
any follow-up.  
  
  
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