Clinical trial NCT03326245
Conditions: Normal Physiology
Keywords: Pharmacological MRI C-11 Raclopride PET Imaging Neuropsychological Testing
Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Start date: 2018-01-29; Completion date: 2024-02-08
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Background:

Dopamine (DA) is a chemical signal in the brain linked to learning, memory, and habits. Stimulant drugs like methylphenidate can increase DA in the brain. Researchers want to measure DA with and without this drug. They want to learn how methylphenidate and brain dopamine affect body responses, mood, and thinking.

Objective:

To better understand the role of dopamine in the brain and the effects of methylphenidate.

Eligibility:

Adults ages 18-55 who have used alcohol or stimulant drugs but have no drug dependence.

Design:

Participants will be screened with:

* Physical exam
* Question about medical, psychiatric, and alcohol and drug use history
* Questions to see if it s safe to have a PET/MRI scan
* Blood and urine tests
* Breath test for alcohol

Participants will have 3 or 4 study visits. At each visit they will have:

* Urine and breath tested for alcohol and drugs
* A thin plastic tube (catheter) inserted in each arm by needle
* A small amount of radioactive chemical injected through the catheter.
* PET/MRI scan. Participants will lie still on a table that slides in and out of a metal cylinder surrounded by a strong magnetic field. Their vital signs will be monitored. They will get earmuffs for loud noises. Before the scan, participants will get the study drug or placebo through the catheter. They may also get a sugar pill (placebo). They will get a small meal and have blood drawn.
* Tests of memory, attention, and thinking.

Participants will wear an activity monitor on the wrist for one week.

Detailed description:
Objectives: The overarching goal of this study is to assess the dynamic association between dopamine (DA) D2 receptor (D2R) occupancy measured by positron emission tomography (PET) with \[11C\]raclopride and brain activity inferred by pharmacological magnetic resonance imaging (phMRI) in the human brain, and to assess the relative sensitivity and specificity of the neurovascular coupling for slow (oral) versus rapid (intravenous, IV) stimulant methylphenidate (MP) delivery. Secondary objectives are to assess the associations between behavioral measures (heart and respiration rates and blood pressure, motor and sleep parameters, and neuropsychological testing variables), D2R occupancy and fMRI signals.

Study population: 10 healthy males and 10 healthy females 18-55 years old will be included. Test-retest reproducibility studies will be carried out in 5 participants.

Design: Double-blind. Participants will undergo simultaneous PET/phMRI, to evaluate dynamic changes in D2R occupancy by DA with \[11C\]raclopride and in blood-oxygenation-level dependent (BOLD) signals, under MP or placebo (PL). The participants will be scanned on 3 different occasions: 1) oral-MP (60 mg) and iv PL (3 cc saline), 2) oral-PL and iv-MP (0.25 mg/kg in 3 cc sterile water) and 3) oral PL and iv PL, which will be carried in different study days with at least 48 hours between them and their order will be randomized across subjects. Participants and researchers will be blind to the nature of the stimulant drug (MP/PL).

Outcome parameters: The scale factor between the distribution volume ratio (DVR) and the BOLD signal in the dorsal and ventral striatum for the slow and fast MP challenges.

Arms: arm 1: Healthy participants receive methylphenidate 60mg orally given 30 minutes prior to bolus \[11C\]raclopride injection followed by intravenous placebo (3ml saline) given 30 minutes post bolus injection of \[11C\]raclopride. PET/phMRI scan (MRI and PET scan) was initiated at the start of the \[11C\]raclopride injection. Participants were subsequently randomized across study arms B and C in different study days with at least 48 hours between visits. arm 2: Healthy participants receive oral placebo given 30 minutes prior to bolus \[11C\]raclopride injection followed by intravenous methylphenidate 0.25 mg/kg in 3ml sterile water given 30 minutes post bolus injection of \[11C\]raclopride. PET/phMRI scan (MRI and PET scan) was initiated at the start of the \[11C\]raclopride injection. Participants were subsequently randomized across study arms A and C in different study days with at least 48 hours between visits. arm 3: Healthy participants receive oral placebo given 30 minutes prior to bolus \[11C\]raclopride injection followed by intravenous placebo (3ml saline) given 30 minutes post bolus injection of \[11C\]raclopride. PET/phMRI scan (MRI and PET scan) was initiated at the start of the \[11C\]raclopride injection. Participants were subsequently randomized across study arms A and B in different study days with at least 48 hours between visits.
Interventions: intervention 1: Methylphenidate Pill intervention 2: Oral Placebo intervention 3: Intravenous Placebo intervention 4: Intravenous methylphenidate
Intervention descriptions: intervention 1: Oral methylphenidate (60 mg) given 30 minutes prior to bolus \[11C\]raclopride intervention 2: Oral PL will be given 30 minutes prior to bolus \[11C\]raclopride injection intervention 3: Intravenous Placebo given 30 minutes post bolus injection of \[11C\]raclopride. intervention 4: Intravenous methylphenidate 0.25 mg/kg in 3ml sterile saline given 30 minutes post bolus injection of \[11C\]raclopride.

Protocol documents:
Prot_SAP_000.pdf: 
17-AA-0178 (2/23/2022)
Protocol Title:  Dopaminergic Modulation of Brain Activation using Simultaneous 
PET/pharmacological MRI
Abbreviated Title: Simultaneous PET/phMRI
Protocol Number: 17-AA-0178
Date of This Submission/Version:  23FEB2022 / Version 10 – AM 12 
Principal Investigator
Name, Degree
Branch/Institute
Bldg/Rm
Phone
E-mail
Dardo Tomasi, PhD
LNI/NIAAA
10/B2L124
301-496-1589
tomasidg@mail.nih.gov  
Total requested accrual:  40 Healthy controls, for an estimated completion of 25
Project Uses Ionizing Radiation: 
No 
Yes
IND/IDE
No 
Yes 
Drug/Device/#   54,135 ([11C]raclopride)
Sponsor:  NIH CC
  
Drug/Device/#   124,912 (IV Methylphenidate)
Sponsor:  NIAAA
Durable Power of Attorney 
No 
Yes
Multi-institutional Project
No 
Yes
Data and Safety Monitoring Board 
No 
Yes  
Technology Transfer Agreement 
No 
Yes  
Samples are being stored 
No 
Yes
Flesch-Kincaid reading level of consent form: Healthy Volunteers = 8.1


17-AA-0178 (2/23/2022)
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Précis:

Objectives:  The overarching goal of this study is to assess the dynamic association 
between dopamine (DA) D2 receptor (D2R) occupancy measured by positron emission 
tomography (PET) with [11C]raclopride and brain activity inferred by pharmacological 
magnetic resonance imaging (phMRI) in the human brain, and to assess the relative 
sensitivity and specificity of the neurovascular coupling for slow (oral) versus rapid 
(intravenous, IV) stimulant methylphenidate (MP) delivery.  Secondary objectives are 
to assess the associations between behavioral measures (heart and respiration rates and 
blood pressure, motor and sleep parameters, and neuropsychological testing variables), 
D2R occupancy and fMRI signals. 

Study population: 10 healthy males and 10 healthy females 18-55 years old will be 
included. Test-retest reproducibility studies will be carried out in 5 participants. 

Design:  Double-blind. Participants will undergo simultaneous PET/phMRI, to 
evaluate dynamic changes in D2R occupancy by DA with [11C]raclopride and in blood-
oxygenation-level dependent (BOLD) signals, under MP or placebo (PL). The 
participants will be scanned on 3 different occasions: 1) oral-MP (60 mg) and iv PL (3 
cc saline), 2) oral-PL and iv-MP (0.25 mg/kg in 3 cc sterile water) and 3) oral PL and 
iv PL, which will be carried in different study days with at least 48 hours between them 
and their order will be randomized across subjects. Participants and researchers will be 
blind to the nature of the stimulant drug (MP/PL). 

Outcome parameters:  The scale factor between the distribution volume ratio (DVR) 
and the BOLD signal in the dorsal and ventral striatum for the slow and fast MP 
challenges.
Table of Contents 
Précis:.........................................................................................................................................................2
List of Abbreviations (if applicable).................................................................................................3
1. Introduction and Background.......................................................................................................4
2. Study Objectives.................................................................................................................................4
3. Subjects.................................................................................................................................................7
4. Study Design and Methods...........................................................................................................10
5. Management of Data and Samples ............................................................................................18
6. Additional Considerations ...........................................................................................................19
7. Risks and Discomforts...................................................................................................................19
8. Subject Safety Monitoring ............................................................................................................24
9. Outcome Measures .........................................................................................................................25
10. Statistical Analysis .......................................................................................................................25
11. Human Subjects Protection.......................................................................................................26
12. Anticipated Benefit ......................................................................................................................28


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13. Consent Documents and Process ............................................................................................28
14. Data and Safety Monitoring.......................................................................................................29
15. Quality Assurance.........................................................................................................................30
16. Reportable Events........................................................................................................................30
17. Alternatives to Participation....................................................................................................31
18. Privacy..............................................................................................................................................31
19. Confidentiality...............................................................................................................................31
20. Conflict of Interest........................................................................................................................32
21. Technology Transfer ...................................................................................................................32
22. Research and Travel Compensation ......................................................................................33
23. References ......................................................................................................................................36
24. Attachments/ Appendices.........................................................................................................36
25. Consent Forms...............................................................................................................................36
List of Abbreviations
ADHD
attention deficit hyperactivity disorder
BOLD
blood-oxygenation-level dependent
CANTAB
Cambridge Neuropsychological Test Automated Battery
CBF
cerebral blood flow
CBV
cerebral blood volume
D2R
dopamine receptor
DA
dopamine
DAT
dopamine transporter occupancy
DTI
diffusion tensor imaging
DVR
distribution volume ratio
fMRI
functional magnetic resonance imaging
iv
intravenous
MP
methylphenidate
MSN
medium spiny neurons
NAc
nucleus accumbens
PET
positron emission tomography
phMRI
pharmacological magnetic resonance imaging
PK
pharmacokinetics
PL
placebo
SN
substantia nigra
TAC
time activity curves


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1. Introduction and Background
Over the last 2 decades, studies using positron emission tomography (PET) have 
demonstrated a relationship between methylphenidate (MP) pharmacokinetics (PK), 
dopamine transporter occupancy (DAT) and the behavioral effects of MP, as well as 
its effects at the synaptic level [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. MP is used in 
the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy and its 
uptake in the brain has similar regional distribution as that of cocaine [7].  Like cocaine, 
MP blocks the DAT, and increases synaptic DA in the striatum, including the nucleus 
accumbens [20].  PET studies in humans have demonstrated that cocaine’s and MP’s 
rapid uptake in the striatum parallels the euphoria [21. 22] whereas their brain clearance, 
which is much faster for cocaine (half-life 20 minutes) than for MP (90 minutes) does 
not. However, whereas the fast brain clearance of cocaine allows for frequently 
repeated administration [23], the slow clearance of MP results in target saturation, which 
may underlie its lower abuse liability compared to cocaine [7].  PET studies also showed 
that cocaine [24] and MP decrease cerebral blood flow (CBF) in striatum and cerebellum 
[25, 26].   More recently, functional magnetic resonance imaging (fMRI) has been used 
to investigate the effect of MP on brain activity.  These studies have shown that oral 
administration of MP produced regional increases in the blood oxygenation level-
dependent (BOLD) response in rodents [27], healthy subjects [28, 29, 30, 31, 32, 33, 34, 35, 36] 
and ADHD patients [31, 37, 38, 39, 40, 41].  However, no changes or reductions in brain 
activation were also observed during motor (finger tapping), reward, and reversal 
learning tasks [42, 43, 44], suggesting that MP’s effects on brain activation depend on the 
nature of the fMRI task. MP has also been shown to alter ‘resting-state’ functional 
connectivity (FC), as captured with fMRI, to reduce FC in ventral striatum, and to 
normalize hypo FC in ADHD patients [45, 46, 47, 48, 49, 50, 51]. Likely, MP’s PK and its 
regional effects on brain activity play significant roles in its therapeutic and behavioral 
effects. However, little is known about how the synaptic and molecular specific actions 
of MP captured with PET translate into BOLD-fMRI responses, because the BOLD-
fMRI signal depends complexly on blood oxygenation, CBF, and volume (CBV; see 
below Neurovascular Coupling). Moreover, the functional effects triggered by MP-
induced increases in DA will depend on whether there is a predominance of signaling 
from D1 (D1R) or from D2 receptors (D2R); whereas DA binding to D1R is 
stimulatory to medium spiny neurons (MSN) in striatum, DA binding to D2R is 
inhibitory.   In turn DA’s binding to D1R versus D2R will be affected by the route of 
administration since DA will bind to D1R, which are low affinity, only when there are 
large DA increases, as achieved with intravenous (iv) MP; whereas it will bind to D2R, 
which are high affinity, even with relatively low DA increases as achieved by oral but 
also iv MP.  We hypothesize that BOLD-phMRI signal changes will be correlated with 
DA displacement in the striatum and that this effects will differ for oral than for iv MP. 
This study will provide novel PET/phMRI methodology for investigating 
neurovascular coupling in health and disease conditions.
Dopaminergic effects of stimulant drugs
DA neurons located in the ventral tegmental area (VTA) and substantia nigra (SN) of 
midbrain project to the ventral and the dorsal striatum via the mesolimbic and 
nigrostriatal pathways, respectively.  The rewarding and conditioning effects of drugs 


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seem to be predominantly driven by transient and pronounced increases in DA cell 
firing that stimulate D1R in the nucleus accumbens (NAc) [52, 53].   In contrast, DA 
stimulation of D2R in NAc appears to be implicated in inhibiting aversive responses 
and in sustaining motivation [54].  In humans, PET studies that take advantage of 
radiotracers that bind to D2R/D3R that are sensitive to binding competition from 
endogenous DA, such as [11C]raclopride, have shown that stimulants, such as MP, 
increase DA in dorsal striatum and in ventral striatum (where NAc is located) and that 
these increases are associated with the subjective rewarding effects of the drugs when 
given iv [3, 55, 56] but not when given orally [57]. 
The blood oxygenation level-dependent (BOLD) contrast is the most commonly used 
technique to non-invasively study brain function. For activated regions, the local 
increases of CBF and CBV largely exceed the local increase in oxygen consumption, 
producing a decrease in paramagnetic deoxyhemoglobin concentration, which 
increases the homogeneity of the local magnetic field, and consequently the local fMRI 
signal [58, 59, 60, 61]. This dynamic signal increase is the basis of the BOLD contrast that 
is widely used to study the effects of pharmacological challenges such as MP, on brain 
function in humans. Pharmacological MRI (phMRI) is a technique that allows 
researchers to noninvasively map brain function in response to the hemodynamic 
changes brought on by the introduction of a pharmaceutical challenge. phMRI is 
analogous to fMRI but employing pharmacological methods of stimulation, phMRI 
maps the time course and neurological response to specific pharmacological challenges 
and gives insight into the pharmacokinetic and pharmacodynamic properties of drugs 
aimed at brain diseases. It is unclear, however, how peripheral and cardiovascular 
changes induced by acute MP administration affect the BOLD signal.  Oral MP, which 
is the route used for therapeutic effects, only triggers mild increases in blood pressure 
[62]. In contrast, iv MP (0.5 mg/kg) triggers significant increases in systolic blood 
pressure and heart rate (HR), which parallel closely MP’s PK in the brain, and induces 
"high" and changes in diastolic blood pressure, which decrease rapidly despite long-
lasting binding of the drug in the brain [1].  We have been doing studies with iv MP for 
20 years and have not experienced any serious adverse events when using MP doses of 
0.5 mg/kg iv.  Nonetheless, considering that the study will be carried in the more 
challenging PET/phMRI environment we propose to use a lower dose of iv MP (0.25 
mg/kg), which is a dose we have also shown induced significant increases in DA [17], 
in order to minimize the chances of adverse cardiovascular (HR and BP increases) or 
behavioral effects (i.e. anxiety, panic).   Quantitatively, an MP dose of 0.25 mg/kg of 
MP corresponded to about 50% occupancy and that of 1 mg/kg to about 80% 
occupancy. We feel confident the 0.25 mg/kg dose will be sufficient to elicit similar 
responses to those of the 0.5 mg/kg dose. Compared to the 0.25mg/kg dose the 0.5 
mg/kg dose has stronger cardiovascular effects which we wish to minimize considering 
that the study will be carried in the more challenging PET/phMRI environment. Thus, 
we propose to use the 0.25 mg/kg MP dose in order to minimize the chances of adverse 
cardiovascular (HR and BP increases) or behavioral effects (i.e. anxiety, panic).  For 
oral MP, we will use a 60 mg dose, which we have shown induced significant increases 
in DA [12].  This dose is within the high range of doses used therapeutically in adults 
with ADHD [63].  We have not experienced any serious adverse events when using MP 


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doses of 60 mg po.
The neurovascular coupling is the relationship between neural activity and 
hemodynamic signals. The interactions between these variables are complex and 
involve a number of interrelated factors [64]. The basal ganglia have been studied 
widely in humans and nonhuman primates using PET radiotracers and are a natural 
target for PET/phMRI studies on the neurovascular coupling. Using simultaneous PET 
and MRI with pharmacological doses of a DA D2R antagonist (raclopride), Sander et 
al. [65] demonstrated that phMRI can provide a good surrogate for the D2R measures 
traditionally obtained with PET. The coupling between D2R blockade and the 
consequent cerebrovascular responses in the striatum presumably reflected changes in 
neuronal/glial activity [66]. Specifically, Sander et al found increased striatal CBV after 
the raclopride challenge, consistent with the CBF striatal increases/decreases in 
primates after administration of D2R antagonists/agonists [67, 68], and with the notion 
that antagonism of D2R signaling would disinhibit D2R mediated inhibition of striatal 
D2R-expressing MSNs [69].  Taken together with prior results, these findings indicate 
that antagonism of D2R signaling in the primate brain leads to striatal activation. In the 
striatum, D2R are predominantly expressed in postsynaptic GABAergic neurons 
(MSN), which project to the external globus pallidus, where DA binding to D2R 
inhibits MSN activity.   D2R are also expressed in DA terminals (autoreceptors) and in 
cortico-striatal glutamatergic terminals, where DA binding, respectively, inhibits DA 
and glutamate release [70]. Thus, increased CBV in striatum with D2R blockade could 
reflect not only disinhibition of D2R-expressing MSN but also enhanced cortico-
striatal glutamatergic signaling, as well as increased DA release with a resultant 
increase in stimulatory D1R signaling. In addition, D2R are also expressed in 
acetylcholine and GABA interneurons (2–4% of the total neuronal population in 
striatum), which could also contribute to striatal activation/deactivation signals. 
Hypothesizing that 1) fast- and short-lasting DA increases triggered by i.v. MP will 
engage stimulatory D1R in ventral striatum, and 2) slow- and long-lasting DA 
increased triggered by oral MP will engage D2R in dorsal striatum, we predict that the 
neurovascular coupling between the dynamic PET and MRI signals will be opposite 
for i.v. (positive linear scale factor) than for oral (negative linear scale factor) MP. 
Detection of phMRI changes produced by MP is challenging using the endogenous 
BOLD contrast because small CBV changes (<10%) are expected to cause even smaller 
BOLD signals (<1%) [71]. To enhance the CBV signals, Sander et al. [65] injected 
coated superparamagnetic iron oxide nanoparticles in the blood stream of the 
anesthetized primates [72], an approach not currently feasible in humans. 
Simultaneous PET/phMRI
PET and phMRI are highly complementary and their combination is a powerful 
scientific tool to understand mechanisms underlying the BOLD signal and its 
relationship to a drug’s PK. While PET uses radioactive tracers and labeled drugs to 
map synaptic elements involved in neurotransmission (receptor, transporters, etc.) with 
high sensitivity and chemical specificity, it suffers from low spatial and temporal 
resolution (2-10mm; 1 minute). In contrast, BOLD-phMRI does not use ionizing 
radiation and can map brain function with high spatial and temporal resolution (0.3-


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3.0mm; 1 second) but suffers from low sensitivity and specificity [73]. Thus, the 
simultaneous PET/phMRI acquisition aims to overcome the limitations of each 
individual technique and advance understanding the dynamic actions of drugs on 
BOLD responses in the human brain. Together, PET and MRI measures have the 
potential to help clarify the neurochemical basis of BOLD signal changes induced by 
MP and other stimulant drugs. Cutting-edge PET/MRI technology, such as the 3-T 
Siemens Biograph mMR or General Electric SIGNA PET/MR scanners installed at the 
NIH Clinical Center, features PET detectors that are installed within the MRI bore [74] 
that can operate both modalities simultaneously without significant performance 
impact [74].  However, the accuracy of attenuation correction in a combined PET/MRI 
examination remains unclear. Some suggest that the attenuation correction problem is 
potentially solved for the brain by predicting bone information from anatomic MR 
images [75, 76, 77] while others think that attenuation correction based on the MRI Dixon 
sequence is not sufficiently accurate [78].  Whereas attenuation correction remains a 
potential concern for quantitative PET, the present approach is based on a dynamic 
response change (comparisons with itself) that is resilient to attenuation correction 
problems [65, 79].
2. Study Objectives 
a. Primary objectives
To quantify the dynamic association between dopamine D2R occupancy measured 
by PET and brain activity inferred by phMRI in the human brain (aim 1); and to 
assess the relative sensitivity and specificity of the neurovascular coupling for 
slow (oral) versus rapid (intravenous, IV) stimulant MP delivery (aim 2).
b. Secondary objectives
To assess the associations between physiological and behavioral measures (BP, 
HR, and subjective behavioral effects), D2R occupancy by DA, and phMRI 
signals, and the reproducibility of the signals across PET/MRI instruments.
3. Subjects
a.
Description of study populations 
A total of 20 healthy volunteers (10 males and 10 females) will be studied.  The 
accrual number for the study will be 40, which is the estimated necessary number 
to complete studies in 20 subjects and the reproducibility studies in five (n=5) 
subjects. We expect that 1/2 of the subjects that undergo screening will not 
complete the study or don't fulfill criteria.  NIH employees may participate in this 
study.
b.
Inclusion criteria
Healthy Volunteer Participants
1.
Males or females between 18 and 55 years of age.
2.
Ability to provide written informed consent.
3.
Willing to abstain from drug use on scheduled testing days.


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4.
Have or had any prior experience with alcohol use or stimulant drugs 
including cocaine, methylphenidate, amphetamine or methamphetamine, 
diet pills (prescription or over the counter), caffeine, and others but did not 
have a substance use disorder.
c.
Exclusion criteria 
1.
Pregnant or breastfeeding.  Females of childbearing potential must have 
negative urine pregnancy test and not be currently breastfeeding. Post-
menopausal or surgically sterile (tubal ligation or hysterectomy) females 
satisfy these criteria.  
2.
Unwilling or unable to refrain from use within 24 hours of scheduled study 
procedures: psychoactive medications or medication that may affect study 
results (e.g., antibiotics (must finish course at least 24 hours prior to a 
scheduled procedure), antidiarrheal preparations, anti-inflammatory drugs 
[systemic corticosteroids are exclusionary], anti-nausea, cough/cold 
preparations) (self-report, medical history). The following medications are 
allowable for entry on this study:  analgesics (non-narcotic); antacids; 
antiasthma agents that are not systemic corticosteroids; antifungal agents 
for topical use; antihistamines (non-sedating); H2-Blockers/PPI (proton 
pump inhibitors); laxatives. The use of antihyperlipidemics and/or diuretics 
are permitted if they have been taken for at least 1 month before procedure 
visits and dose has been stabilized. The episodic use of benzodiazepines 
such as alprazolam (™Xanax), diazepam (™Valium) and lorazepam 
(™Ativan), will not exclude participants from this study unless they have 
been taken within the last 24 hours prior to the study.
3.
The following current chronically used medications are exclusionary from 
the study: stimulant or stimulant-like medications (amphetamine, 
methylphenidate, modafinil); analgesics containing narcotics; anorexics 
(sibuteramine); antianginal agents; antiarrhythmics; antiasthma agents that 
are systemic corticosteroids; antibiotics; anticholinergics; anticoagulants; 
anticonvulsants; antidepressants; antidiarrheal preparations; antifungal 
agents (systemic); antihistamines (sedating); antihypertensives; anti-
inflammatory drugs (systemic); antineoplastics; antiobesity; antipsychotics; 
antivirals (except for treatment of HSV with agents without CNS activity, 
e.g. acyclovir, ganciclovir, famciclovir, valacyclovir); anxiolytics 
(benzodiazepine or barbiturates); hormones (exceptions: thyroid hormone 
replacement, oral contraceptives, and estrogen replacement therapy); 
insulin; lithium; muscle relaxants; psychotropic drugs not otherwise 
specified (nos) including herbal products (no drugs with psychomotor 
effects or with anxiolytics, stimulant, antipsychotic, or sedative properties); 
sedatives/hypnotics.  Note that nicotine and/or caffeine use will not exclude 
participants.
4.
Current or past DSM-IV or DSM-5 diagnosis of a psychiatric disorder as 
determined by history and clinical exam including substance use disorder 
(except for nicotine/caffeine), alcohol use disorder (or alcohol dependence 
if assessed using DSM-IV), anxiety disorder or panic attacks.  Past history 


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of a mental disorder as defined by DSM-IV or DSM-5 will be excluded only 
if it required hospitalization (any length), or chronic medication 
management (more than 4 weeks), and that could impact brain function at 
the time of the study. 
5.
Those with a binge drinking history every month continuously for the last 
10 years will also be excluded. Binge drinkers are those who being female 
consume 4 or more drinks and males consume 5 or more drinks in one 
occasion at least once a month.
6.
Major medical problems that can impact brain function at the time of the 
scan (including but not limited to HIV; glaucoma, central nervous system 
including seizures and psychosis; cardiovascular including hypertension 
and arrhythmias; metabolic, autoimmune, endocrine) as determined by 
history and clinical exam.
7.
Any clinically significant laboratory finding as determined during the 
screening procedures.
8.
Have had previous radiation exposure (from X-rays, PET scans, or other 
exposure) that, with the exposure from this study, would exceed NIH annual 
research limits.
9.
Head trauma with loss of consciousness for more than 30 minutes.
10.
Presence of ferromagnetic objects in the body that are contraindicated for 
PET/phMRI of the head (pacemakers or other implanted electrical devices, 
brain stimulators, some types of dental implants, aneurysm clips, metallic 
prostheses, permanent eyeliner, implanted delivery pump, or shrapnel 
fragments), fear of enclosed spaces, or other standard contraindication to 
MRI/MRS (self-report checklist).
11.
Cannot lie comfortably flat on back for up to 2 hours in the PET/phMRI 
scanner.
12.
Body weight > 204 kg (> 450 lbs).  
13.
Allergy to methylphenidate.
14.
Clinically significant EKG abnormalities.  Clinically significant findings on 
EKG will be assessed by the Medical Advisory Investigator on the study or 
through a cardiology consult.  EKG reviews are documented in CRIS.
15.
History of glaucoma as determined by medical history.
16.
NIH employees who are study investigators, as well as their superiors, 
subordinates and immediate family members (adult children, spouses, 
parents, siblings).
17.
Non-English speakers (must also be able to read and comprehend English).  
* Subjects will not be excluded from enrollment in this study if their urine 
test is positive for drugs.  However, if they test positive on scheduled study 
procedure days involving study imaging and neuropsychological testing, 
the procedures will be postponed and rescheduled.  We will allow for up 
to 3 rescheduled study days that were the result of positive urine drug 
screens. If the drug test is positive on the third rescheduled visit, the 
participant will be withdrawn from the study.  The intent of the research 
has no prospect of direct benefit to the subject. Therefore, we are excluding 


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non-English speakers in this research study since it includes the 
administration of questionnaires, surveys and assessments that are 
validated for English, although some are available in Spanish. In addition, 
our fMRI paradigms (particularly the Delay Discounting task) require that 
the subject be able to speak, read and comprehend English.
4. Study Design and Methods
a.
Study overview 
Participants will be tested with simultaneous [11C]raclopride-PET/phMRI to map 
the dynamics of DA receptor occupancy (reflecting extracellular DA levels) and 
BOLD signals using the MP challenge (oral and iv).  During the study, 
participants will also undergo a neuropsychological battery and personality tests, 
which are detailed below.  Time points are targets, and the order can be adjusted 
for practical considerations. The studies will be conducted as outpatients.
b. Recruitment
Participants will be recruited through referrals from the NIH Volunteer Office, 
the Patient Recruitment and Public Liaison (PRPL) Office, and through 
ResearchMatch.org.  
Participants (including healthy volunteers who are NIH employees) will also be 
recruited by word of mouth and through IRB-approved advertisements. These 
will include: 1) Flyers posted on NIH campus, campuses of universities and 
colleges, public places and public transportation services in the greater 
Washington DC/Baltimore metro areas; 2) Advertisements in electronic and 
printed local media (newsletters, websites, newspapers, craigslist.org, NIH and 
other local email distribution lists), following IRB approval. There will be no 
direct solicitation of employees by supervisors or coworkers.
ClinicalTrials.gov may also represent a source of recruitment.
Participants will also be recruited via the 14-AA-0181 Natural History protocol.  
c.
Telephone Pre-Screening
Initial contact with potential subjects will be done through use of a telephone 
pre-screening questionnaire.  Subjects will be briefly interviewed over the 
telephone to determine that they report meeting inclusion and not meeting 
exclusion criteria as described above.  Subjects who appear to meet criteria will 
be scheduled for a screening visit.  Subjects who do not meet criteria based on 
this telephone interview will not be scheduled for a screening visit and their 
telephone screening form will be shredded in a cross-cut shredder. A waiver of 
consent for these screening activities has been requested in Section 13.
d. Screening 


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1. Screening Procedures performed under present study or Protocol #14-
AA-0181 (NIAAA Natural History protocol):  Consent will be obtained 
prior to any study procedures are done.  As of 12/14/2021, we will not screen 
under 14-AA-0181 since initial eligibility was done in all subjects prior to this 
date. Procedures will include diagnostic assessments for psychiatric 
disorders, patient medical history and physical examination including EKG 
and standard laboratory tests (Chem Screen; CBC; TSH; PT; PTT; cholesterol 
levels, high sensitivity C-reactive protein, homocysteine & Urinalysis) and, 
for female participants of childbearing potential, a urine pregnancy test. 
STAT urine tests to identify drug abuse (cocaine, methamphetamine, 
amphetamines, opioids, cannabinoids, benzodiazepines and barbiturates). 
Urine tests will be repeated on each day of study at least once to ensure lack 
of drug use.  We will not repeat the screening tests that have already been 
done under the NIAAA Natural History protocol (14-AA-0181). Clinical or 
non-clinical tests performed under 14-AA-0181 are valid for one year.  
Missing or outdated screening tests will be done under the present study.  The 
following information and test results, which may be collected under the 
present study or the Natural History protocol #14-AA-0181, will be shared 
with this study:
Demographics  
Vital signs:  heart rate, blood pressure, pulse, temperature
Measurements:  height, weight, BMI
Bloodlabs:  Blood test panels to assess physiological functions and screen 
for clinically significant disease presence. No more than 30 mL will be 
drawn.  The blood tests include:
o
Complete blood count with differential (CBC with diff) PT, PTT. 
o
Chem 20 Panel (Chem 20): Sodium (Na), Potassium (K), Chloride 
(Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea nitrogen 
(BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic 
Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid, 
amylase.  
Urine test
o
Urinalysis this is a series of tests done on urine to screen for 
abnormalities – results received next morning and reviewed.
o
Urine drug screens: The Qualitative (DLM) tests for benzodiazepines, 
cocaine, methamphetamines, opiates and tetrahydrocannabinol 
(THC). It provides a result within hours.  Urine drug screens will be 
performed on subsequent days of study – STAT.
o
Pregnancy test. This is required by Clinical Center regulations prior 
to MRI and PET scanning – STAT.  If sample is processed by DLM, 
result is provided within hours.  
Electrocardiogram (EKG)
MR Safety Questionnaire – this will be obtained during initial screening 
and on each day that PET/phMRI is done – takes 5 min.


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Questionnaires, Assessments, Interviews (all subjects):  If any of the 
following are obtained through the Natural History protocol, we will only 
repeat if too much time has passed since initially done. Some of these 
questionnaires, assessments and interviews do not require repeating since 
the answers don’t change over time.  Drug History interview, rating 
scales, diagnostic interview and self-report questionnaires are as follows:
o
MR Safety Questionnaire.
o
Edinburgh Handedness Scale [80].
o
Smoking History Questionnaire [81] – takes 10 min.
o
Fagerström Test for Nicotine Dependence (FTND) [82] – takes 5 min.
o
Adult ADHD Self-Report Scale (ASRS-v1.1) - The Symptom 
Checklist is an instrument consisting of the eighteen DSM-IV-TR 
criteria.  Six of the eighteen questions were found to be the most 
predictive of symptoms consistent with ADHD. These six questions 
are the basis for the ASRS v1.1 Screener and are also Part A of the 
Symptom Checklist. Part B of the Symptom Checklist contains the 
remaining twelve questions [83].
o
The Timeline Follow-Back (TLFB) technique collects drinking and 
smoking information using personal historical events recounted over 
a fixed time period [84, 85].  It is a commonly used technique to assess 
alcohol drinking patterns and quantification in treatment programs. 
This questionnaire may need an update if more than a year has passed 
since last completed by the participant who will return for scans on 
the GE PET/MR scanner.
o
Alcohol Use Disorders Identification Test (AUDIT) [86].
o
Structured Clinical Interview (SCID): The SCID is a widely-used, 
standard clinical interview to establish criteria for psychiatric 
diagnoses [87].  It is a structured interview consisting of 11 modules 
and up to as many as 292 questions that take between 60 and 180 
minutes to complete. 
2. Study Evaluations and Procedures:  Consent for the current study will be 
obtained prior to starting study procedures under this study.  All information 
and results of screening tests described in section 4.d.1 Procedures performed 
under NIAAA Natural History protocol #14-AA-0181 above will be shared 
with this study and reviewed for eligibility criteria discussed in section 3. 
Subjects above.  If any of the lab tests done under the NIAAA Natural History 
protocol are missing or outdated (performed more than 1 year prior to current 
date), the tests will be done under this study for ongoing eligibility.  All tests 
obtained under NIAAA Natural History protocol #14-AA-0181 will be 
reimbursed under that protocol.  Clinical and non-clinical tests performed 
under this protocol will be reimbursed under this protocol.  
The following procedures will be done on each day of study once consent has 
been obtained:
Vital signs - daily:  heart rate, blood pressure, pulse, temperature


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Measurements - daily:  height, weight, BMI 
Brief Medical/Physical HX - daily
Breath alcohol test
Urine tests - daily
o
Urine drug screens: The Qualitative (DLM) tests for benzodiazepines, 
cocaine, methamphetamines, opiates and tetrahydrocannabinol 
(THC). It provides a result within hours.  Urine drug screens will be 
performed on each day of study – STAT.
o
Pregnancy test:  This is required by Clinical Center regulations prior 
to MRI and PET scanning – STAT.  Urine pregnancy test will be 
performed on any day of study involving imaging scans and/or drug 
dosing.  
Electrocardiogram (EKG) – this will be done on each day that involves 
drug dosing followed by PET/phMRI.  This will be started prior to drug 
dosing through to end of the imaging scan.
MR Safety Questionnaire – this will be obtained and reviewed on each 
day that PET/phMRI is done prior to participation in PET/phMRI – takes 
5 min.
Drug History (HX) Parts I & II – takes about 15 min.  
o
Drug HX Part II will be obtained on each subsequent visit – takes 
about 5 min. Only Drug HX Part II will be repeated in participants 
returning to repeat the scans on the new GE PET/MR scanner.
Note: Bulleted arrow items in sections 4.d.1 & 4.d.2 above that are shaded in 
pale yellow will be done to confirm ongoing eligibility for subjects returning to 
repeat the scans on the new GE PET/MR scanner. The bulleted items starting 
from Edinburg Handedness Scale down through the SCID do not have to be 
repeated for participants since they were obtained in these subjects previously. 
The exception to this list is the Timeline Follow Back which may need an 
update to satisfy exclusion #5 which deals with alcohol drinking history.
Once it has been determined that the subject meets/maintains the criteria and all 
standard laboratory test results have been received/reviewed and they indicate 
the subject has no clinically significant lab results that would interfere with 
study participation, they will be considered enrolled and subsequently 
scheduled to start imaging procedures.  If a subject has visited the NIH CC 
recently and had some clinical and/or non-clinical tests performed, we plan to 
use the existing results for determining eligibility. If a subject’s most recent 
visit is greater than a year, we will order new lab tests if needed for ongoing 
eligibility. As standard operating procedure (SOP), the NIH Clinical Center 
requires that a clinical MRI scan of the brain, which is a minimal risk procedure 
and may include any standard clinical MR sequence as well as Diffusion Tensor 
Imaging (DTI) sequences, must be done on all enrolled subjects.  This clinical 
scan can be done at any time prior to completion of the study.  In general, we 
plan to obtain this clinical MRI scan on the day that PET/phMRI scanning is 
scheduled, but it could be done on another day too.


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e.
Study Timeline:  This research study will take place over four or more days 
including screening.  After initial screening, subjects will be expected to come 
to the Clinical center 3 or more days for the PET/phMRI scans, and NPT and 
personality tests.    If the imaging scans and NP tests cannot be completed on 
the days they are scheduled, then the subject might have to come on another day 
to finish the procedures.  All PET/phMRI scans, DNA from blood, NP testing 
results and personality measures obtained will be for research purpose only and 
the results will not be shared with the participants.  Participants who return for 
repeat scans on the new GE scanner will not repeat NP tests, personality 
measures genotyping or GENEActiv activity monitoring. Study visits will be 
planned as follows:

Initial Study Screening 

*Study Procedures Day A:  PET/phMRI Scanning Session

*Study Procedures Day B:  PET/phMRI Scanning Session

*Study Procedures Day C:  PET/phMRI Scanning Session
*Note:  The order of Days A, B and C will be randomized.  In addition, the 
NP testing can occur in any of the 3 study days that subjects are scheduled 
for PET/phMRI, or on another day.  
1. Screening Visit (Day 1 for all): First, informed consent is obtained followed 
by initial study screening.  Participants will be screened for eligibility as 
delineated in the inclusion and exclusion criteria for the study.   Once 
eligibility has been confirmed, and the subject agrees to continue 
participation, he/she will be scheduled for the PET/phMRI scanning sessions 
and NP testing as outpatients.
The orders for these three days of scanning will be randomized
2. PET/phMRI Scans:  PET/phMRI scanning will be carried out on a 3Tesla 
(3T) Siemens Biograph mMR or General Electric SIGNA PET/MR scanner 
installed in the Clinical Center. MRI evaluations of the brain are being 
performed at 3T.  These MRI scans are performed on FDA-approved scanners 
with approved radiofrequency coils, and their use conforms to the 
corresponding FDA labels. The MR scanner is being used in normal mode 
(not research mode) using the following FDA magnetization-prepared rapid 
gradient-echo (MPRAGE) pulse sequences and echo-planar imaging (EPI).
In preparation for the PET/phMRI scans, a catheter will be placed into the 
subject’s antecubital vein (venous catheter) for tracer injection. Tracer 
administration of [11C]raclopride will be injected over a period of 
approximately 1-2 minutes using an FDA approved infusion pump with an 
approximate delivery range of 9-16 mCi of [11C]raclopride. At the start of 
[11C]raclopride injection, a dynamic PET scan will be initiated (list mode). 
Ultrashort (UTE) or zero (ZTE) echo-time imaging will be used to map 


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structures with short T2 relaxation times such as bone [88]and used for 
attenuation correction during PET retrospective image reconstruction. 

Study Procedures DAY A:  Oral MP (60 mg) will be given 30 
minutes prior to [11C]raclopride injection followed by iv placebo 
(PL) given 30 minutes post injection of [11C]raclopride.

Study Procedures DAY B:  Oral PL will be given 30 minutes prior 
to [11C]raclopride injection followed by iv MP (0.25 mg/kg) given 
30 minutes post injection of [11C]raclopride.

Study Procedures DAY C:  Oral PL will be given 30 minutes prior 
to [11C]raclopride injection followed by iv PL given 30 minutes post 
injection of [11C]raclopride.
A high resolution T1-weighted magnetization-prepared rapid gradient-echo 
pulse sequence will be used to map brain structure with high spatial resolution 
and excellent gray-white contrast. Single-shot echo planar imaging (3mm 
isotropic resolution; TE/TR= 30/3000ms) will be used to collect functional 
images continuously during 100 minutes to measure brain activation and to 
map functional connectivity using a single-shot T2*-weighted EPI pulse 
sequence. MRI and PET acquisitions will start at the same time. The 
PET/phMRI scan will be done under dim illumination. We will monitor heart 
rate and blood pressure using an MRI compatible non-invasive blood pressure 
monitor.  In the event of an adverse event we will immediately contact the 
cardiologist on call from the clinical center or initiate the emergency response 
as clinically indicated.
Rating Scales:  To assess the effects of MP before and after PET/phMRI scans 
we will use self-rating indicators of drug effects (Drug Evaluation 
questionnaire) and the Profile of mood Scale (POMS), which is adapted from 
the Profile of Mood States (89).  
Food control: A standard small meal will be provided for the subjects about 
3 hours prior to the scheduled PET/phMRI scans.  We will provide a 300-500 
calories snack (choices salad or sandwich). Subjects will be asked to fast from 
the time s/he wakes up in the morning until we provide this standard meal.  
After PET/MRI is complete, subjects may be provided with a meal if they are 
hungry. 
3. Genetic Testing (Genotyping – collected on any Day of study):
Since the inter-subject variability of the FC partially reflects genetic 
variability, the genetic profile of the individuals could help us understand the 
mechanism underlying diversity in DA signaling and in brain functional 
connectivity. As information on new genes involved with DA signaling and 
brain function emerge we can then assess the role of relevant genetic 
polymorphisms on brain dopamine, functional connectivity and energetic 
efficiency.


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All participants will be asked to give a total of 10 ml of blood split into two 
vials containing 5 ml each (1 teaspoon) for genetic research purposes.  The 
genetic material, DNA, will be extracted from one of the samples and 
analyzed in order to assess the role of relevant genetic polymorphisms on 
brain dopamine, BOLD signals and energetic efficiency. Leftover DNA and 
the other 5 ml sample will be stored at -80Co for future use. Genetic samples 
will be analyzed at NIH.  Subjects will consent to keep their sample so that in 
the future we can analyze them for yet-to-be-discovered polymorphisms 
associated with behavioral and imaging data.  The results from this research 
study will be preliminary.  Further research may be necessary before they are 
fully understood. The genetic testing that will be done as part of this study is 
for research purposes only and results will not be placed in the medical record.  
Genetic testing is optional.
Genetic testing will not be done in participants who return to repeat scans on 
the new GE PET/MR scanner.
4. Neuropsychological Tests:  NP tests will be done either on the day of the 
PET/phMRI scans (before the scans) or asked to come on a separate day.  
These tests will not be done following the oral MP administration.  We will 
use the Cambridge Neuropsychological Test Automated Battery (CANTAB), 
which is a computerized battery of tests [90]. The CANTAB has normative 
data and has good reliability [91, 92] and is sensitive to drug effects [93].  We 
will obtain the following CANTAB tests:  

Reaction Time –Multiple choices reaction time test.  

Stop Signal- it's a measure of response inhibition

Intra/Extra-Dimensional Set Shift –Attention test, similar to the 
Wisconsin Card Sorting Test.  

Pattern Recognition Memory –Stockings of Cambridge – Visuospatial 
planning test that is on the ‘Tower of London’ test.   

Spatial Span –Spatial working memory span test.  

Spatial Working Memory –This is a test of a subject's ability to retain 
and to manipulate spatial information in working memory. 

Cambridge Gamble Task, test of decision making

Affective Go/No-go – test for emotional bias

Emotion Recognition Task –test to assess social cognition
Additional NP measures not included in CANTAB:

Barratt’s Impulsiveness scale will be used to assess impulsivity [94]. If 
this has been collected under the Natural History protocol, it will not be 
repeated.

The Beck Depression Inventory Second Edition (BDI-II) is a 21-
question multiple-choice self-report inventory for measuring the 
severity of symptoms of depression as listed in the DSM-IV [95].  In case 
BDI-II scores are 20 or higher, indicating moderate to severe 


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depression, or in case of suicidal thoughts (that is, a scoring of 2 "I 
would like to kill myself" or 3 "I would like to kill myself if I had the 
chance" on item 9), the participant will be seen by a psychiatrist or nurse 
immediately for follow-up and appropriate clinical referrals.  Please 
note, however, that before the BDI-II is filled out, all participants have 
been screened with the SCID, and with MADRS scores of 20 or higher.

The Wechsler Abbreviated Scale of Intelligence-Second Edition 
(WASI-II) is a widely used brief measure of cognitive abilities [96] and 
has excellent reliability and validity. The two subscales “Vocabulary” 
and “Matrix Reasoning” will be used, which yield a full scale IQ score. 
It takes about 20 minutes to complete.
http://www.cambridgecognition.com/?gclid=CNH9qq-
96roCFWrNOgodvHsA8Q 
Personality Measures:

Morningness-Eveningness Questionnaire (MEQ), which provides a 
self-report circadian typology that is based on the preferred timing for 
activity, sleep/wake preferences, and optimal timing for mental 
alertness [97]. Responses to these items are considered to represent 
underlying circadian function.   

The NEO-PI Five Factor Inventory (FFI) organizes personality traits 
into five domains: Neuroticism, Extraversion, Openness to Experience, 
Agreeableness, and Conscientiousness [98]. 

Multidimensional personality questionnaire (MPQ), which three main 
personality 
dimensions: 
Positive 
Emotionality 
or 
PEM 
(or 
extraversion), Negative emotionality or NEM (or neuroticism) and 
constraint [99]. These measures tap into characteristics associated with 
vulnerability to substance use disorders and correlate with specific 
patterns of brain activity [100].
NP testing and Personality tests will not be done in participants who return 
to repeat scans on the new GE PET/MR scanner.
5. Motor Activity and Sleeping Behavior measured with ™GENEActiv:  To 
assess spontaneous motor activity we will ask participants to wear a  
GENEActiv accelerometer [101] for one week either prior or after completion 
of the scans. The recording from the GENEActiv will also allow us to 
determine the average number of hours slept per day and their levels of 
spontaneous motor activity. The GENEActiv measures can be obtained prior 
to or after completion of the PET/phMRI scans.  
GENEActiv procedures will not be done in participants who return to repeat 
scans on the new GE PET/MR scanner.
f.
End of participation


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Clinically relevant information may be shared with receiving health care 
providers if in clinical assessment this is for the benefit of the patient, and the 
patient consents to this.
Potential Future Contact:  While all steps are always taken to ensure quality data 
from all participants, we may ask participants who generate unusable data (or if 
there is an equipment failure) on one of their experimental sessions to repeat that 
session.  This will have the effect of maximizing the risk/benefit ratio as it will 
prevent having to discard usable data from one session and will minimize the 
number of participants recruited overall to obtain sufficient data to meet power 
requirements.  We may ask the participant to return at a later date or to repeat 
study procedures for genotyping, PET/phMRI scans. There may only be one 
repeat scan per participant. Subjects will receive additional compensation if 
experimental sessions are repeated; compensation for this as needed research 
procedures may vary based on the inconvenience units and will be based on 
NIAAA recommendations. 
5. Management of Data and Samples
a.
Storage
Data will be stored on an NIH data server, under the management of the ORIT, 
NIAAA. The existence and types of information contained in the data 
management system have been publicly reported as required by the FOIA.
Subject data will be stored in one of two locations. Fully identifiable data will be 
stored in the NIH Clinical Center CRIS system, where clinical patient data are 
routinely stored and adequate privacy protections are implemented by design.  
Additional data will be stored in the B2L124 NIAAA/LNI space in Building 10 
on an access controlled NIAAA server located in secured space to prevent 
physical theft of storage media.  We will feed some of the data residing in CRIS 
and on the NIAAA servers to the NIH Biomedical Translational Research 
Information System (BTRIS).  Data on the NIAAA server will be kept in a coded 
form. The code key will be kept separately by the trial leader or designee.
Biological specimens obtained under this protocol will be stored in coded form 
(protocol identifier plus randomization number), in freezers located in Bldg 10 
CRC Room 15281 area of NIAAA.  We will collect 10 ml of venous blood from 
each participant, which will be divided into 2 parts; one of which will be frozen 
and stored at -80ºC and the other to be used for DNA isolation and subsequent 
genotyping tests. 
We will collect DNA so that in the future when new findings emerge with respect 
to genes implicated in brain diseases so we can assess across integrated data from 
various brain imaging studies if they are associated with changes in brain 
connectivity.  However, DNA collection will be optional and will not exclude 


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subjects from participating in this study if they do not want to give blood for 
genotyping.
b.
Data including genomic data and sample sharing plan
Samples and data, including genomic data may be shared with collaborators. 
Data and samples may also be shared with collaborating laboratories at NIH or 
outside of NIH and/or submitted to NIH-designated repositories and databases if 
consent for sharing was obtained.  Repositories receiving data and/or samples 
from this protocol may be open-access or restricted access. 
Samples and data will be stripped of identifiers and may be coded (“de-
identified”) or unlinked from an identifying code (“anonymized”). When coded 
data is shared, the key to the code will not be provided to collaborators, but will 
remain at NIH.  Data and samples may be shared with investigators and 
institutions with an FWA or operating under the Declaration of Helsinki (DoH) 
and reported at the time of continuing review.  Sharing with investigators without 
an FWA or not operating under the DoH will be submitted for prospective IRB 
approval.  Submissions to NIH-sponsored or supported databases and repositories 
will be reported at the time of Continuing Review.  Submission to non-NIH 
sponsored or supported databases and repositories will be submitted for 
prospective IRB approval.
Required approvals from the collaborating institution will be obtained and 
materials will be shipped in accordance with NIH and federal regulations.
6. Additional Considerations
a. Research with investigational drugs or devices
[11C]raclopride is injected into the subject’s bloodstream to produce the images 
that are captured by the PET scan. The radiotracer [11C]raclopride is used for 
imaging D2R, under the IND 54,135.
IV methylphenidate (MP), used under IND #124,912, is injected into the subject’s 
bloodstream to be used in conjunction with PET imaging to show displacement 
of [11C]raclopride.  We received approval from the FDA for the use of iv 
methylphenidate under the IND #124,912. 
7. Risks and Discomforts
Potential risks from this study include the following: 
a. Medical examination and Laboratory testing: Medical examinations are 
associated with minimal risks. We will first explain and familiarize the subjects 
with the laboratory testing to minimize discomfort, if any, during testing. Tests 
may disclose that the potential subject’s health is at risk.  If there are abnormal 
tests uncovered as part of the physical examination, this information will be 


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given to the subject and explained by a physician who will encourage them to 
seek medical evaluation with their primary care physician.
b. PET/phMRI Risks:  People are at risk for injury from the MRI magnet if they 
have pacemakers or other implanted electrical devices, brain stimulators, some 
types of dental implants, aneurysm clips (metal clips on the wall of a large 
artery), metallic prostheses (including metal pins and rods, heart valves, and 
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel 
fragments.  Welders and metal workers are also at risk for injury because of 
possible small metal fragments in the eye of which they may be unaware.  
Subjects will be screened for these conditions before having any scan, and if 
he/she has any, he/she will not receive the PET/phMRI scan.  If a subject has a 
question about any metal objects being present in his/her body, he/she should 
inform the staff.  In addition, all magnetic objects (for example, watches, coins, 
jewelry, and credit cards) must be removed before entering the PET/phMRI 
scan room. 
It is not known if MRI is completely safe for a developing fetus.  Therefore, all 
women of childbearing potential will have a pregnancy test performed no more 
than 24 hours before each PET/phMRI scan.  The scan will not be done if the 
pregnancy test is positive. 
People with fear of confined spaces may become anxious during a PET/phMRI.  
Those with back problems may have back pain or discomfort from lying in the 
scanner.  The noise from the scanner is loud enough to damage hearing, 
especially in people who already have hearing loss.  Everyone having a research 
PET/phMRI scan will be fitted with hearing protection.  If the hearing 
protection comes loose during the scan, the subject should let a member of the 
staff know right away.  The subject will be asked to notify the investigators if 
he/she has hearing or ear problems.  The subject will be asked to complete an 
MRI screening form for each MRI scan he/she has.  There are no known long-
term risks of MRI scans. 
PET detects injected radioactivity within the body. PET is associated with no 
known physical hazards to the subject lying on the table. We routinely use a 
series of procedures to minimize the risk for discomfort during scanning 
sessions. Namely, the procedures are conducted in the presence of trained health 
professionals to whom subjects will have ready access, should they experience 
any problems. Subjects can communicate with the trained health professionals 
while in the scanner and can be removed from the scanner or withdraw from 
the study at any time if they wish to do so.  Occasionally subjects become 
anxious during the scan. In that case, subjects can request the operator of the 
PET/phMRI to stop the scan.
c.
Radiation exposure risks:  The consent form uses wording approved by the NIH 
Radiation Safety Committee to communicate to the subject the risk associated 


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with this radiation exposure.  Radiation exposure will be from a maximum of 
64 mCi of [11C]raclopride.  This amount includes a contingency plan for an 
additional scan if we need the subject to repeat a day of PET/phMRI study.  This 
is expected to happen infrequently.  In subjects who complete the PET/phMRI 
scan protocol, the effective dose from emission scans on a maximum of 4 days 
of study will be 1.3 rem. No harmful effects to humans have been observed 
from the levels of radiation used in this study.  Additional measures taken to 
ensure subject safety will be to obtain a careful history of exposure to radiation 
from other sources or medical procedures to ensure that total exposure remains 
within an acceptable range. Pregnancy and breastfeeding are exclusion criteria 
for women of child-bearing potential. Using the standard way of describing 
radiation dose, from participating in this study, subjects will receive a maximum 
of 7.5 rem to their gallbladder wall, 6.1 rem to their small intestine and 4.2 rem 
to their liver. All other organs will receive smaller amounts of radiation.  
d. Venous line placements:  In preparation for the PET/phMRI scan, one catheter 
is placed into the subject in an antecubital vein (venous catheter) in one arm for 
radiotracer injection. A second catheter is placed in the other arm on the day the 
subject receives study drug (either placebo or oral MP 60 mg, or iv 
methylphenidate 0.25 mg/kg) for blood sampling levels of placebo or MP in 
plasma before, during and at the end of study.  There is a slight risk of bruising 
or, rarely, infection from insertion of indwelling peripheral venous catheters for 
infusion. Risks from IV catheterization are minimized by experienced medical 
personnel who will perform catheter placement using sterile technique and 
following universal precautions. Participants will be seated or supine when 
catheters are placed.
e.
Oral MP exposure: MP (brand name Ritalin) is a widely used stimulant drug 
used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and 
Narcolepsy.  For treatment of ADHD, and when given as immediate release 
tablets (as per the current study) the typical doses correspond to 10-20 
milligrams (mg) two to three times a day (typical oral doses of 60 mg/day up to 
maximal oral doses of 1g/day). Methylphenidate hydrochloride (HCl) is 
available as a generic or by the brand name Ritalin™ and is FDA approved.  
Methylphenidate is a Class II controlled substance. MP will be purchased from 
a commercial vendor and will be stored in the NIH Pharmacy.  Inventory and 
accountability records are maintained by the Pharmacy as per DEA regulations.  
Administration of the active drug (methylphenidate HCl):  The active drug will 
be administered as a commercial tablet(s) over-encapsulated in a hard gelatin 
capsule, with common inactive excipients added to protect the blind.
Placebo formulation:  A hard gelatin capsule, identical to that used for over-
encapsulation of the active drug tablet(s), containing inactive ingredients, 
primarily anhydrous lactose.  The inactive ingredients will be the same as those 
used in the active drug formulation.


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Adverse Events related to oral MP administration:  The most common adverse 
reactions of MP are: Hypersensitivity; skin rash, urticaria (hives, an allergic 
skin eruption), fever;  Central Nervous System (CNS): dizziness, headache, 
dyskinesia (impairment of voluntary movement), drowsiness; Cardiovascular: 
blood pressure and pulse changes; tachycardia; angina; cardiac arrhythmias; 
palpitations; Gastro-Intestinal (GI): nausea, anorexia (loss of appetite); and 
Miscellaneous: nervousness and insomnia.  The side effect that is most common 
is increased heart rate and blood pressure.  Once consent has been obtained for 
this study he/she will received an EKG to exclude subjects who may have heart 
abnormalities.  This initial EKG may have been obtained through the NIAAA 
Natural History Protocol #14-AA-0181. In addition, if the subject has a history 
of heart trouble or hypertension requiring medication, he/she will be excluded 
from participation.  Heart rate and blood pressure will be monitored during MP 
administration (prior to receiving study drug through to the end of imaging 
study) as a procedure on PET/phMRI study days.  Clinically significant findings 
on any EKG, heart rate or blood pressure will be assessed by the MAI on the 
study or through cardiology consult.  A physician/CRNP with current 
certification in advanced cardiac life support (ACLS) will be present during the 
study.  Other Warnings: As stated in the methylphenidate monograph in "Facts 
and Comparisons" 2004:  Hypersensitivity - arthralgia; exfoliate dermatitis; 
erythema multiforme with histopathological findings of necrotizing vasculitis; 
thrombocytopenia purpura.  Less common Leukopenia and/or anemia; scalp 
hair loss; abnormal liver function, ranging from transaminase elevation to 
hepatic coma; cerebral arteritis and/or occlusion; transient depressed mood; 
neuroleptic malignant syndrome (very rare).  Contraindications to MP 
(MicroMedex):  MP should not be given to individuals using monoamine 
oxidase inhibitors (MAOI’s, e.g., phenelzine and tranylcypromine) or to those 
with a history of seizures, tics, agitation, psychotic disorders, glaucoma, 
cardiovascular disorders, hypertension, and arrhythmia since it can exacerbate 
those symptoms.  To minimize the possibility of an untoward reaction we will 
exclude subjects with past or present histories of these conditions.  
f.
INTRAVENOUS (iv) MP Exposure (0.25 mg/kg): In this study, participants will 
be given an iv MP dose of 0.25 mg/kg through the catheter in the arm on study 
Day B.  This is a route of administration that results in stronger behavioral and 
cardiovascular effects that when given orally; and participants may feel “high” 
and excited.  Participants may even experience anxiety or become overexcited 
and restless after iv MP.  Some participants describe this as unpleasant because 
it makes them feel anxious and out of control, and rarely, it may result in 
paranoid ideas.  In addition, the same side effects described above for oral MP 
can occur with iv MP. Participants will be asked not to exercise for the next 24 
hours (including dancing or partying) following oral or iv MP or the only 
placebo day session (Study Procedures Day 3) and not to take any drugs, 
including alcohol, after the studies.  Sudden increases in BP may be potentially 
harmful.  Participants may feel the effects of iv or oral MP for about 3 to 4 hours 


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after its administration. If a participant has a history of seizures, anxiety, panic 
attacks or psychosis or glaucoma, MP could make these conditions worse.  If a 
participant has any of these conditions, he/she will be excluded from this study.  
Also since MP typically increases HR and BP, he/she will be excluded from 
this study if he/she has a history of heart disease including arrhythmias or 
hypertension or if clinically significant abnormalities in a participant’s EKG or 
in their BP are detected prior to the PET/phMRI study.  HR and BP will be 
monitored during the scanning.  A physician with certification in advanced 
cardiac life support (ACLS) will be present in the PET/phMRI laboratory at all 
times during the study.  After injection with MP, the physician or CRNP will 
remain in the scanning room with the participant for at least 30 minutes; this 
will not be necessary for oral MP since the cardiovascular effects are much 
milder.  If a participants BP increases and remains above 180 or falls below 60 
for 10 minutes, or his/her HR increases above 180 beats/minute or becomes 
irregular, or he/she shows abnormal clinical signs of discomfort, the study will 
be stopped, symptoms will be treated immediately, and he/she will not be 
permitted to continue in the study.  Participants will be monitored and will not 
be allowed to leave the NIH Clinical Center until vital signs have stabilized.  If 
a participant has an unexpected adverse reaction to MP, the study will be 
stopped immediately and he/she will not be permitted to complete any 
remaining parts of the study. 
Contraindications:  MP should not be given to individuals with a history of 
seizures, 
psychotic 
disorders, 
glaucoma, 
cardiovascular 
disorders, 
hypertension, and arrhythmia since it can exacerbate those symptoms.  To 
minimize the possibility of an untoward reaction we will exclude subjects with 
past or present histories of these conditions.  
g. Genotyping (genetic tests):  The genetic testing that will be done as part of this 
study is for research purposes only and results will not be placed in the medical 
record. It will not provide any information about the participant’s health or 
ancestry.  It is our policy to not provide the results of such genetic testing to 
study participants.  Problems, such as with insurance or employment 
discrimination, may occur if a participant discloses information about this 
genetic testing or if he/she agrees to have his/her medical records released.  We 
will not release any information about a participant to any physician, insurance 
company or employer unless he/she signs a document allowing release of the 
information.
h. NP and personality measures: These tests are not harmful, but may be 
frustrating or stressful. Subjects may refuse to answer any question that makes 
them uncomfortable and may stop a test at any time and for any reason.
i.
Blood Banking for Future Genetic Studies:  This will allow us to repeat our 
genetic tests, thus to ensure and validate the genotyping results.  In addition, we 
will be able to conduct analyses of new variations in the brain related genes that 


17-AA-0178 (2/23/2022)
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are yet to be discovered.   Blood samples will be stored in secured freezers on 
the NIH campus. The participants name and identifying information will not be 
on the samples; we will assign them a code.  The key to the code will be kept 
in a separate, secure area.  The samples may be used for other research 
projects.  If participants do not want his/her sample used for other projects, 
he/she should not participate in this study.  If a participant withdraws from this 
research project before it is complete, any remaining samples he/she have 
contributed will be discarded.  Results obtained before he/she withdraws will 
be kept and the participant’s privacy will be protected.
8. Subject Safety Monitoring
Subjects’ safety will be monitored by the medical advisory investigator (MAI).
Parameters to be monitored for all participants before, during and at the end of the 
study sessions will include vital sign (heart rate, blood pressure and temperature).
If any participant reports an adverse reaction to the experiment or demonstrates 
adverse responses during the post-experimental assessment of adverse events (AE), 
or appears to be in distress at any point during the experiment, the procedures will 
stop and the patient will meet with the medical advisory investigator to assess 
suitability for continuation in the study. Additionally, procedures will be stopped for 
any participant who asks to stop them at any point.  The reasons for participants’ 
discontinuation from the study will be logged and changes to procedures necessary 
to prevent future adverse reactions will be made.
Any individual may withdraw from the study at any time and with no penalty.  This 
option is clearly stated in the consent form and will be emphasized to participants.
NCI Common Terminology Criteria for Adverse Events v. 3.0 will be used for 
grading and reporting adverse events (CTCAE, 2007).
Criteria for individual subject withdrawal

Significant AE, including clinically significant changes in mood or behavior 
such as aggression, agitation, depression or suicidal ideation or suicidal 
behavior or clinically significant changes in heart rate (>180), BP (Systolic 
>180 < 60) or arrhythmias (2 consecutive readings of blood pressure 
parameters).

Three positive drug screens.

Pregnancy.

At the discretion of the Principal Investigator (PI) and Medical Investigator, 
based on adverse event (AE) severity.

Non-compliance with protocol procedures or investigator request(s).

Patient request.

Repeated positive drug screens.


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9. Outcome Measures
a.
Primary outcome measures:
To assess:
o
The distribution volume ratios (DVR).
o
The %BOLD signal change after MP (oral and iv).
o
The %DVR change after MP (oral and iv).
o
The temporal correlation between BOLD(t) and DVR(t).
o
The test-retest reproducibility of MP-related changes in %BOLD and 
DVR.
b.
Secondary outcome measures
To assess: 
o
The correlation between DVR(t) and behavioral measures (heart rate, BP, 
and respiration rate).
o
The correlation between BOLD(t) and behavioral measures (pupil size, 
eye blinks, heart rate, blood pressure, and respiration rate).
10. Statistical Analysis
a.
Analysis of data/ study outcomes
The PET and phMRI reconstructed images will be spatially normalized to match 
the stereotactic space of the Montreal Neurological Institute (MNI) with 3-mm 
isotropic voxels framing intervals of 1 min. The PET data will be analyzed using 
the cerebellum as a reference region, where D2R concentration is 103 times 
smaller than in the striatum. Thus, [11C]raclopride has negligible specific binding 
in the cerebellum. A graphical method that does not require blood sampling 
[102]will be used for determining DVR(t). Linear trends will be removed to 
minimize first-order scanner signal drifts.  Then the signal change from baseline 
will be used to compute the combined PK/PD responses [%BOLD(t) and 
DVR(t)].  The PK/PD response to oral MP should be an inverted U-shape, 
peaking ~90 minutes after ingestion (i.e. ~40 minutes after the start of EPI 
acquisition and ~60 minutes after the start of the dynamic PET scan). We will 
also quantify the area-under-the-curve (AUC), and the peak values for the 
%BOLD(t) and DVR(t) signals. The effect of Oral MP will be computed by 
contrasting estimates from Days A and C; the effect of IV MP will be computed 
by contrasting estimates from Days B and C.  For instance, for the effect of oral 
MP on BOLD signals we will contrast BOLD estimates from Day A versus those 
from Day C; for the effect of iv MP on DVR signals we will contrast DVR 
estimates from Day B versus those from Day C. Paired t-test (with BP, HR and 
respiration frequency covariates to control for potential effects of PaCO2 on 
BOLD responses) will be used for statistical testing on these intermediate 
measures. One-sample t-test (fixed effects) will be used to test Hypothesis 1A: 
“The %BOLD(t) signal change will increase in proportion to %DVR(t) change in 
the striatum”. Statistical significance will be set by PFWE < 0.05, corrected for 
multiple comparisons using the random field theory with a family-wise error 
correction. One sample t-test (random effects) will be used to test Hypothesis 1B 


17-AA-0178 (2/23/2022)
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“The scale factor between %BOLD(t) signal changes and %DVR(t) changes in 
the striatum will be statistically significant across subjects”. Statistical 
significance will be set by PFWE < 0.05.  We expect that the DA increases triggered 
by i.v. MP will engage stimulatory D1R in ventral striatum, and that those 
triggered by oral MP will engage D2R in dorsal striatum.  This would result in 
opposing scale factors for i.v. (positive linear scale factor) than for oral (negative 
linear scale factor) MP. Paired t-test (random effects) will be used to test 
Hypothesis 2: “The scale factor for oral MP will differ from that for iv MP”. 
Specifically, whereas iv MP will trigger short lasting and immediate increases in 
%BOLD(t) signal in ventral striatum (where NAc is located) after injection, oral 
MP will trigger slow and long lasting decreases in %BOLD(t) signals in striatum.
Correlation analysis will be used to assess the reproducibility of PET and MRI 
signals collected with different PET/MRI instruments (the Siemens Biograph 
mMR and General Electric SIGNA PET/MR).
b.
Power analysis 
Within-subjects: The statistical power of the proposed  sample size  will allow us 
to detect  effect sizes > 0.63 (Hypothesis 1A), 0.66 (Hypothesis 1B) and 0.62 
(Hypothesis 2) which are significantly lower than the correlations between 
CBV(t) and the time activity curves (TAC) previously reported for the striatum 
(R > 0.6) for different pharmacological doses of raclopride in macaques [65].
Our effect size estimations (based on data from 2 macaques) for the reported 
correlations between CBV(t) and the time activity curves (TAC) by Sander et al 
[65] is ~ 2. Different from Sander et al [65], superparamagnetic nanoparticles will 
not be used to boost the MRI signal in this study. Thus, our conservative power 
analysis includes a smaller effect size that accounts for the expected noisier 
BOLD(t) signals. 
11. Human Subjects Protection
a.
Subject selection
Adults (age 18-55) who fulfill the eligibility criteria will be included, regardless 
of race, ethnicity, sex, or religious affiliation.   We predict the racial composition 
is approximately 60% Caucasian, 35% African American, and remaining 5% 
proportion of Asian or other.  We predict the Hispanic ethnicity to be 
approximately 25%.  On the same basis, the expected breakdown is 50% male 
and 50% female.  The upper age limit of 55 years of age was chosen to minimize 
cardiovascular side effects from the administration of iv MP, which are more 
common in older subjects.  
b.
Justification for exclusion of children
Children are excluded because the study is more than minimal risk without benefit 
to the individual child, thus making the risks outweigh the benefits of the study.
c.
Justification for exclusion of other vulnerable subjects 


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Subjects that are mentally ill may have severe impairment of cognitive function, 
which would interfere with those individuals’ ability to give consent. Their ability 
to consent may also change over time. Subjects that are mentally ill may also 
require hospitalization. .  . Subjects with body weight > 204 kg (>450 lbs) are 
excluded since this is the weight limit of the PET/phMRI scanner.
d.
Justification for sensitive procedures 
This study employs [11C]raclopride and oral and iv MP to evaluate D2R 
occupancy as a function of increases in extracellular DA.  
e.
Safeguards for vulnerable populations and sensitive procedures 
Vulnerable populations such as pregnant women will not be studied due to the 
potential unknown risks of radiation and of MP exposure to this population.  
Urine Pregnancy tests will ensure women who may be pregnant are excluded 
from the study.  We will rely on self-report for women who are breast feeding 
and they too will be excluded.
This study is open to NIH staff to participate as healthy volunteers. NIH OHSRP 
policy 404 permits the participation of NIH employees to participate in NIH 
studies unless prohibited by their IC. There is no such policy in our institute. We 
will follow Policy 404 Research Involving NIH Staff as Subjects. Prior to 
enrollment, we will request that the NIH staff member review the “Leave Policy 
for NIH Employees Participating in NIH Medical Research Studies (NIH Policy 
Manual 2300-630-3”, and we will provide a copy of the  “NIH Frequently Asked 
Questions (FAQs) for Staff Who are Considering Participation in NIH Research 
for their review. Although NIH employees may participate, study investigators 
and their superiors, subordinates and immediate family members (adult children, 
spouses, parents, siblings) will be excluded.  Protections for employees and staff 
participating in this study include 1) assuring that the participation or refusal to 
participate will have no effect, either beneficial or adverse, on the subject’s 
employment or position at the NIH, 2) giving employees and staff who are 
interested in participating the “NIH Frequently Asked Questions (FAQs) for Staff 
Who are Considering Participation in NIH Research” prior to obtaining consent, 
and 3) assuring that there will be no direct solicitation of employees or staff. Co-
workers will not obtain consent. 
This study collects sensitive information on drug/alcohol use, medical, neurologic 
and psychiatric histories.  The PI will train study staff regarding obtaining and 
handling potentially sensitive and private information about co-workers through 
staff discussions and written branch/section procedures.  In addition, all staff will 
have completed the "Just in time" human subject’s protection training course on 
"Biomedical- Vulnerable Subjects-Workers/Employees" through CITI prior to 
engaging in recruitment of NIH employees.  Privacy and confidentiality for NIH 
Employees will be adhered to the same as for other subjects.  The certificate of 
confidentiality (CoC) that will be applied for this study will be used to resist 
demands for subject information as allowed by law.


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12. Anticipated Benefit
There is no direct benefit to the subjects participating in the study.  The results of the 
study may improve our understanding of brain function in healthy conditions. Thus, 
the research is likely to yield generalizable knowledge.
13. Consent Documents and Process
a.
Consent procedures 
Participants will be consented on this protocol before any procedures commence.  
They will receive a verbal explanation in terms suited to their comprehension of 
the purposes, procedures and potential risks of the study and of their rights as 
research participants.  Participants will have the opportunity to carefully review 
the written consent form and ask questions regarding this study prior to signing.  
Either the PI or an AI will conduct the consent process in accordance with NIH 
policy.  Only subjects that can give informed consent will be included in this 
study.  The PI and/or AI’s will determine that the subjects are able to give 
informed consent based on their clinical assessment of the subject’s ability to 
understand the nature of the study and the risks.  If the subject’s capacity to 
consent remains questionable, the Ability to Consent Assessment team (ACAT) 
will be consulted. Consent may not be obtained by a co-worker.
Since consenting is an ongoing process, the protocol will be repeatedly re-
explained to participants as needed during the study to reassess their 
understanding of the nature of the protocol.
b.
Consent documents
The consent form contains all required elements.  The original consent is filed 
with their NIH medical record and a digital copy is uploaded into the CRIS 
system. A copy of the signed consent (with subject signature redacted) is also 
made for the subject's research binder for regulatory purposes.
c.
Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study, screening activities listed 
in Section 4c.  may be performed. We request a waiver of consent for these 
activities because based on the nature of the telephone script and questionnaire 
and/or review of the same data available from participation in other research 
protocols at NIAAA, these activities present no more than minimal risk of harm. 
The script informs prospective subjects about the types of questions that will be 
asked and that there are no plans to ask sensitive questions. This research cannot 
be carried out unless we are able to brief the participant, verify their age and 
participation in other NIAAA studies, and gather information such as pregnancy 
status, presence of non-removable metal in their body and verify their ability to 
speak, read and understand English before consenting them in this study. It would 
not be practical to recruit subjects without a preliminary screening to reduce the 
number of potential disqualifications based on the information already available 


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at NIAAA. There are robust confidentiality practices involving limiting access to 
the information obtained during this telephone pre-screening process. Prospective 
subjects will indicate willingness to participate during telephone pre-screening by 
providing verbal consent. Normally, there is no requirement for written consent 
for telephone screening outside the research setting. This waiver will not 
adversely affect the rights and welfare of the subjects. We will not collect and 
store any information from these individuals once their qualification is found 
implausible or they express lack of desire to participate in the study.
14. Data and Safety Monitoring
a.
Data and safety monitor
Data and safety monitoring will be done by an Independent Safety Monitor (ISM) 
Sarah Lisanby, MD, who will review all safety data for each participant yearly.  
Dr. Lisanby has agreed to serve as ISM for this protocol.  Her qualifications 
include that she is a board certified physician licensed in the states of NY and NC 
and she has over 20 years experience conducting clinical research.  Her 
experience includes conducting radiotracer PET studies and studies using 
pharmacological challenge, in which she was responsible for placing arterial 
lines, injecting radiotracers, prescribing medications, performing medical 
assessments on the subjects, identifying and reporting adverse events, and 
clinically managing the patients.    In addition, the Medical Associate Investigator 
(MAI) has over 30 years of experience in PET and MRI imaging and the 
administration of oral and iv methylphenidate. The PI will consult with the  ISM 
and the MAI should any concerns about safety arise.
b.
Data and safety monitoring plan
This study will be monitored on a yearly basis at the time of continuing review. 
We will look at possible trends in AE’s and UP’s to determine if a change to the 
protocol/consent/study procedures becomes necessary via study amendment.  In 
addition, individual subject case report forms will be monitored on an ongoing 
basis upon completion of study visits.  Frequency of monitoring may increase if 
the PI determines it is necessary.
c.
Criteria for stopping the study or suspending enrollment or procedures
This study will be stopped and enrollment suspended if any serious adverse events 
occur that is determined to potentially be related to one of the study procedures.
15. Quality Assurance (QA)
a.
Quality assurance monitor
The Principal Investigator, Lead Investigator and the MAI will be monitoring 
data collection and the study yearly or more often.  Quality assurance (QA) will 
be performed by NIDA QA and NIAAA QA staff as indicated in the NIDA and 
NIAAA Quality Assurance Monitoring Plan on a schedule determined by the 
Clinical Director.  


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b.
Quality assurance plan
Quality assurance (QA) will be performed by the PI, as well as by an independent 
QA monitor, which according to established practice is considered sufficient for 
small, single-site trials, like the present project. The QA monitor for this study 
will have considerable expertise in clinical trials in drug dependence, but s/he will 
not work in the same section of the PI. Therefore, his/her role as QA monitoring 
will assure expertise and independence in the same time.
In addition to yearly monitoring of data collection, the Laboratory of 
Neuroimaging (LNI) utilizes a multi-layer study monitoring program.  As a 
general practice, LNI lab staff records study procedures using a case report form 
(CRF) checklist on the day of each study.  The study procedure checklist is 
completed on the day of study as well as within a few business days after the 
procedures were performed.  Once a subject has completed all procedures per the 
protocol, a final study CRF monitoring log is completed for each participant.  The 
CRF monitoring log captures that procedures were verified, data has been pushed 
to appropriate databases if necessary, questionnaire data entry verified if 
necessary, and the participant CRF folder monitoring log is signed by the LNI lab 
staff who verified the data.  Following that process, each folder is monitored 
independently by other lab staff (i.e., post bac IRTA, clinical protocol 
coordinator, CRNP) as a final independent check that procedures were performed 
per protocol followed by signoff by the Principal Investigator.  
16. Reportable Events
Unanticipated problems, non-compliance, and other reportable events will be 
reported to the NIH IRB as per Policy 801.
It is both the Principal Investigator’s (PI) and the Sponsor’s responsibility to ensure 
the safety of those on the clinical trial.  The PI is responsible for tracking adverse 
events during the study and providing adverse events lists to the Sponsor at regular 
intervals per request. In addition, the PI is responsible for updating the Sponsor 
about known risks from the drug, as discovered from literature searches or other 
means.
In accordance with the requirements of 21 CFR 312.32, the PI or designee will 
report all SAEs, whether or not these are considered related to the investigational 
drug or study intervention, that occur throughout the study to the Sponsor, including 
those events listed in the protocol or Investigator’s Brochure as anticipated to occur, 
as follows: 
Deaths:  within 24 hours of the investigator’s awareness
All other SAEs:  within 48 hours of the investigator’s awareness
All AEs will be sent to the Sponsor quarterly, or at minimum annually, for 
submission to the FDA in the IND Annual Report.


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The PI will immediately report all deaths and SAEs to the Sponsor by disclosing all 
event-related information in a completed MedWatch Form 3500A. This form 
should include the IND number, protocol number, PI name, and an assessment on 
the reasonable possibility of a relationship between the event and the study drug or 
intervention. The completed MedWatch Form 3500A will be sent to the Clinical 
Director/CEO and/or designated medical monitor with a copy to the NIH Office of 
Research Support & Compliance (ORSC) Regulatory Support Section.
The CEO and/or designee will be responsible for determining whether the event is 
reportable to the FDA as an IND Safety Report if it is a serious, unexpected, and 
suspected adverse reaction (SUSAR). If the sponsor determines the SAE meets the 
criteria of a SUSAR, the ORSC will submit an Initial IND Safety Report to the FDA 
no later than 15 calendar days after the PI’s notification of the event to the Sponsor. 
Deaths or life-threatening events will be reported to the FDA no later than 7 calendar 
days after the PI’s notification of the event to the Sponsor. The Sponsor will submit 
any relevant additional information in a Follow-up IND Safety Report no later than 
15 calendar days after receiving the information. All SAEs will be monitored until 
satisfactory resolution. All AEs and SAEs will be documented on appropriate study 
records.
17. Alternatives to Participation 
Participants neither receive nor forego treatment in order to participate in this study.  
The alternative, therefore, is not to participate.
18. Privacy
All research activities will be conducted in as private a setting as possible.
19. Confidentiality
a.
For research data and investigator medical records
Medical records will be handled according to standard NIH Clinical Center 
policies, designed to prevent breach of privacy at a level considered sufficient for 
sensitive health care data.  Investigators will be trained to respect the privacy and 
confidentiality of NIH employees and staff.  Confidentiality and information 
technology standards are in place at the NIAAA and NIDA intramural programs 
to protect electronic repositories of patient data as well as other clinical patient 
related material. It is reasonably expected that these safeguards will protect 
participants' medical and personal health information, ensuring their privacy.  
Information obtained while being screened for or participating in this protocol 
will become part of the patient's NIH medical record.  This includes potentially 
sensitive information, such as results of urine tests that are positive for illicit 
drugs.  Access to this information may be requested by third parties. Such access 
will not be granted without the explicit, written consent of the subjects. However, 


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failure on the part of the subject to provide access to the information may in itself 
be to the disadvantage of the subject, e.g. in the case of a potential employer or 
insurer requesting the information.  This situation will be made clear in the 
consent.
b.
For stored samples
Samples and data will be stored using codes that we assign.  Data will be kept in 
password protected computers.  Samples will be kept in locked storage.  Only 
study investigators will have access to the samples and data.
c.
Special precautions 
The Investigators are applying for a Certificate of Confidentiality (CoC) issued 
by NIH to further protect subject confidentiality.
20. Conflict of Interest
a.
Distribution of NIH guidelines
NIH guidelines on conflict of interest have been distributed to all investigators.  
b.
Conflict of interest 
There are no conflicts of interest to report.
c.
Role of a commercial company or sponsor 
There is no drug company involved.
21. Technology Transfer
This study has a human material transfer agreement (MTA) in place under docket 
number #AA-MTAOUT-21-11005. This MTA is between the National Institute on 
Alcohol Abuse and Alcoholism (NIAAA) ("Provider") and Virginia Commonwealth 
University (VCU) ("Recipient") for the transfer of material isolated from individuals 
who have participated in clinical research (each a "Human Subject''), with or without 
accompanying data, to be used for research purposes and analysis of drug levels and 
endogenous and exogenous compounds (e.g., sex hormones) in plasma. VCU will 
receive coded samples and no access to the code. VCU will have no role or 
participation in the research protocol other than analyzing research blood samples 
for a fee.
22. Research and Travel Compensation 
Volunteers will be compensated for time and research-related inconveniences, to 
the extent to which they complete them, as follows:
Procedures
Inconvenience 
Units
$ 
Payment
Frequency
Total
Screening 
Time involved
3
30
1
30


17-AA-0178 (2/23/2022)
page 33 of 43
Brief History & PE
1
10
1
10
Screening – Total Compensation
$40
Screening Update: (If any clinical/non-clinical tests listed in this section are 
out of date (not performed within 1 year of enrollment) for maintaining 
eligibility, they will be obtained under this study and paid under this study.
Routine Urinalysis 
1
10
1
10
Routine Bloodlabs
4
40
1
40
update Interview/  
  Questionnaires
2
20
1
20
Time Involved
2
20
1
20
Screening Update – Total Compensation up to
$90
GE PET/MR repeat scanning Eligibility
Consent with GE icf 
time involved, 
TLFB update
2
20
1
20
Routine Urinalysis 
1
10
1
10
Routine Bloodlabs & 
EKG
4
40
1
40
GE Eligibility – Total Compensation up to 
$70
Study Procedures DAY A
Urine Drug Screen
1
10
1
10
Urine pregnancy if 
female who can 
become pregnant
1
10
1
10
Brief History & PE, 
Drug HX Part II
1
10
1
10
Intravenous Line 
4
40
1
40
PET/phMRI  
20
200
1
200
MP (60 mg po)
5
50
1
50
Placebo (IV)
5
50
1
50
EKG – continuous
5
50
1
50
DAY A – Total Compensation up to
$ 420
Study Procedures DAY B
Urine Drug Screen
1
10
1
10
Urine pregnancy if 
female who can 
become pregnant
1
10
1
10
Brief History & PE, 
Drug HX Part II
1
10
1
10
Intravenous Line 
Placement(s)
4
40
1
40


17-AA-0178 (2/23/2022)
page 34 of 43
PET/phMRI  
20
200
1
200
Placebo (po)
5
50
1
50
MP (0.25 mg/kg IV)
5
50
1
50
EKG – continuous
5
50
1
50
DAY B – Total Compensation up to
$ 420
Study Procedures DAY C
Urine Drug Screen
1
10
1
10
Urine pregnancy if 
female who can 
become pregnant
1
10
1
10
Brief History & PE, 
Drug HX Part II
1
10
1
10
Intravenous Line 
Placement(s)
4
40
1
40
PET/phMRI  
20
200
1
200
Placebo (po)
5
50
1
50
Placebo (IV)
5
50
1
50
EKG – continuous
5
50
1
50
DAY C – Total Compensation up to
$ 420
Genotyping
Blood Draw Genetic
2
20
1
20
Genotyping – Total Compensation
20
NP and Behavioral
     NP Test Battery
3
30
1
30
     CANTAB –test
3
30
1
30
     NEO-FFI 
1
10
1
10
     MPQ276 
3
30
1
30
     Paper 
questionnaires
3
30
1
30
NP – Total Compensation
130
GENEActiv – 1 week monitoring 
Actinometer
10
100
1
100
GENEActiv – Total Compensation
100
PET/phMRI Make-up Day (contingency plan to make-up Day A, B or C)
Urine Drug Screen
1
10
1
10
Urine pregnancy if 
female who can 
become pregnant
1
10
1
10
Brief History & PE, 
Drug HX Part II
1
10
1
10


17-AA-0178 (2/23/2022)
page 35 of 43
Intravenous Line 
Placement(s)
4
40
1
40
PET/phMRI  
20
200
1
200
Oral drug (MP or PL)
5
50
1
50
IV drug (MP 0.25 
mg/kg or PL)
5
50
1
50
EKG – continuous
5
50
1
50
PET/phMRI Make-up Day (contingency plan) up to
$420
Cancellation – short notice due to fault of NIH
Cancellation fee
20
200
up to 3X
Max $600
Cancellation – compensation
Max $600
Total Compensation to all subjects (consent #1) up to
$2660
Total Compensation to subjects who sign consent #2 (GE 
PET/MR) and repeat the study on the new scanner will earn 
an additional amount up to
$2350
Compensation will be prorated for parts completed if subjects do not complete the 
study.  We have added the potential for up to three short notice cancellation payments 
of $200 each, for a maximum total of $600 if we cancel. We don’t anticipate 
cancelling the study frequently.  This cancellation payment will not be paid when a 
subject cancels on us. If needed, subjects will be provided with a taxi paid for by NIH 
or if they drive, they will be reimbursed for their mileage. Just in case any day of 
study needs to be repeated, we have added that day into the above table and subjects 
could earn a total of up to $2660.  
For the five subjects (n=5) that we bring back to participate in repeating the study on 
the new GE PET/MR scanner in the PET Dept., we will aim to repeat everything 
except for Genotyping, GENEActiv and NP & Behavioral tests. Compensation to 
these subjects will be up to a total of $2350 (see sections shaded in pale yellow). We 
added a section to the chart above to cover consenting for the GE PET/MR scans and 
repeating lab tests that are outdated by over 1 year since last done. This amount takes 
into account the potential for repeating a day of scanning and up to 3 cancellations. 
We don’t anticipate cancelling the study frequently.  This cancellation payment will 
not be paid when a subject cancels on us or fails to meet criteria on the day of study. 
NIH employees or staff who participate during work hours must have permission 
from their supervisor. NIH employees or staff must either participate outside of work 
hours or take leave in order to receive compensation.
23. References
See end of document.


17-AA-0178 (2/23/2022)
page 36 of 43
24. Attachments/ Appendices
a. Eligibility checklists 
Uploaded to iRIS for healthy volunteers.
b. Recruiting advertisements 
Uploaded to iRIS.
c.
Eligibility Exclusion Medications checklist 
Uploaded to iRIS for IRB review.
d. Study Day Medications checklist 
Uploaded to iRIS for IRB review
25. Consent Forms 
Healthy adult volunteer uploaded to iRIS.
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