Dopaminergic Modulation of Brain Activation Using Simultaneous PET/Pharmacological MRI

NCT03326245 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 17017817-AA-0178
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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.

Conditions

Normal Physiology

Keywords

Pharmacological MRI; C-11 Raclopride; PET Imaging; Neuropsychological Testing

Outcome Measures

Primary Outcomes (3)

• The Standardized Uptake Value Ratio (SUVR) for [11C]Raclopride in Putamen

  Participants underwent brain positron emission tomography (PET) scan with \[11C\]raclopride. The SUVR is calculated by dividing the standardized uptake value in the putamen, target region, by the standardized uptake value in the cerebellum, the reference region. This ratio normalizes the uptake values and allows for comparisons between individuals or across different imaging sessions.

  60 min after [11C]raclopride injection

• Percent BOLD Signal Change in the Anterior Cingulum

  The blood-oxygen-level-dependent (BOLD) signal was estimated as the fitted amplitude to the dynamic standardized uptake value ratio (SUVR) change in response to the methylphenidate challenges.

  From 0 to 90 minutes after [11C]raclopride injection

• The Temporal Correlation Between BOLD(t) and SUVR(t) Change

  The Pearson correlation between the temporal dynamics of the blood-oxygen-level-dependent (BOLD) signal in anterior cingulum and the standardized uptake value ratio (SUVR) change in putamen measures changes in the neurovascular coupling induced by methylphenidate.

  From 0 to 90 minutes after [11C]raclopride injection

Study Arms (3)

Arm A: Oral methylphenidate followed by intravenous placebo

ACTIVE COMPARATOR

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.

Drug: Methylphenidate Pill; Drug: Intravenous Placebo

Arm B: Oral placebo followed by intravenous methylphenidate

ACTIVE COMPARATOR

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.

Drug: Oral Placebo; Drug: Intravenous methylphenidate

Arm C: Oral placebo followed by intravenous placebo

PLACEBO COMPARATOR

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.

Drug: Oral Placebo; Drug: Intravenous Placebo

Interventions

Methylphenidate Pill DRUG

Oral methylphenidate (60 mg) given 30 minutes prior to bolus \[11C\]raclopride

Also known as: Ritalin

Arm A: Oral methylphenidate followed by intravenous placebo

Oral Placebo DRUG

Oral PL will be given 30 minutes prior to bolus \[11C\]raclopride injection

Arm B: Oral placebo followed by intravenous methylphenidate; Arm C: Oral placebo followed by intravenous placebo

Intravenous Placebo DRUG

Intravenous Placebo given 30 minutes post bolus injection of \[11C\]raclopride.

Arm A: Oral methylphenidate followed by intravenous placebo; Arm C: Oral placebo followed by intravenous placebo

Intravenous methylphenidate DRUG

Intravenous methylphenidate 0.25 mg/kg in 3ml sterile saline given 30 minutes post bolus injection of \[11C\]raclopride.

Arm B: Oral placebo followed by intravenous methylphenidate

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Current or past Diagnostic and Statistical Manual (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 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.
• 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.
• 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/magnetic resonance spectroscopy (MRS) (self-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 Clinical Research Information System (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).
• Non-English speakers (must also be able to read and comprehend English).

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Manza P, Tomasi D, Shokri-Kojori E, Zhang R, Kroll D, Feldman D, McPherson K, Biesecker C, Dennis E, Johnson A, Yuan K, Wang WT, Yonga MV, Wang GJ, Volkow ND. Neural circuit selective for fast but not slow dopamine increases in drug reward. Nat Commun. 2023 Nov 8;14(1):6408. doi: 10.1038/s41467-023-41972-6.

  PMID: 37938560 RESULT

• Manza P, Tomasi D, Vines L, Sotelo D, Yonga MV, Wang GJ, Volkow ND. Brain connectivity changes to fast versus slow dopamine increases. Neuropsychopharmacology. 2024 May;49(6):924-932. doi: 10.1038/s41386-024-01803-8. Epub 2024 Feb 7.

  PMID: 38326458 RESULT

• Tomasi D, Manza P, Yan W, Shokri-Kojori E, Demiral SB, Yonga MV, McPherson K, Biesecker C, Dennis E, Johnson A, Zhang R, Wang GJ, Volkow ND. Examining the role of dopamine in methylphenidate's effects on resting brain function. Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2314596120. doi: 10.1073/pnas.2314596120. Epub 2023 Dec 18.

  PMID: 38109535 RESULT

• Tomasi D, Manza P, Logan J, Shokri-Kojori E, Yonga MV, Kroll D, Feldman D, McPherson K, Biesecker C, Dennis E, Johnson A, Yuan K, Wang WT, Butman JA, Wang GJ, Volkow ND. Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans. Commun Biol. 2023 Feb 10;6(1):166. doi: 10.1038/s42003-023-04545-3.

  PMID: 36765261 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Methylphenidate

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Dardo Tomasi
• Organization: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

tomasidg@mail.nih.gov

+1 301 496 1589

Study Officials

• Dardo G Tomasi, Ph.D.

  National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2017
• First Posted: October 31, 2017
• Study Start: January 29, 2018
• Primary Completion: December 13, 2021
• Study Completion: February 8, 2024
• Last Updated: May 28, 2024
• Results First Posted: May 28, 2024

Record last verified: 2023-10-27

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)