Dopaminergic Modulation of Brain Activation Using Simultaneous PET/Pharmacological MRI

- Objectives: The overarching goal of this study is to assess the dynamic association
between dopamine (DA) D2 receptor (D2R) occupancymeasured 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.

- Design: Double-blind. Participants will undergo simultaneous PET/phMRI, to evaluate
dynamic changes in D2R occupancy by DA with [11C]raclopride and in bloodoxygenation-
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.

- INCLUSION CRITERIA:

Healthy Volunteer Participants

- Males or females between 18 and 55 years of age.

- Ability to provide written informed consent.

- Willing to abstain from drug use on scheduled testing days.

- 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.

EXCLUSION CRITERIA:

- Pregnant or breastfeeding. Females of childbearing potential must have negative urine
pregnancy test and not be currently breastfeeding. Postmenopausal or surgically
sterile (tubal ligation or hysterectomy) females satisfy these criteria.

- 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.

- 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.

- 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. Those with a binge drinking history in the
last 10 years will also be excluded. Past history 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. Binge drinkers are those who being female consume 4
or more drinks and males 5 or more drinks in one occasion at least once a month.

- 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.

- Any clinically significant laboratory finding as determined during the screening
procedures.

- 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.

- Head trauma with loss of consciousness for more than 30 minutes.

- 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 (elf-report checklist).

- Cannot lie comfortably flat on back for up to 2 hours in the PET/phMRI scanner.

- Body weight > 204 kg (> 450 lbs).

- Allergy to methylphenidate.

- 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.

- History of glaucoma as determined by medical history.

- NIH employees who are study investigators, as well as their superiors, subordinates
and immediate family members (adult children, spouses, parents, siblings).

- 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.