Dopaminergic Modulation of Brain Activation Using Simultaneous PET/Pharmacological MRI

• ClinicalTrials.gov Identifier: NCT03326245
• Recruitment Status: Completed
• First Posted: October 31, 2017
• Last Update Posted: February 12, 2024
• Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Tracking Information

• First Submitted Date: October 28, 2017
• First Posted Date: October 31, 2017
• Last Update Posted Date: February 12, 2024
• Actual Study Start Date: January 29, 2018
• Actual Primary Completion Date: December 13, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 31, 2021)

To assess 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. [ Time Frame: end of study ]

To assess the distribution volume ratios (DVR), the %BOLD signal change after MP (oral and iv), the %DVR change after MP (oral and iv), and the temporal correlation between BOLD(t) and DVR(t).

Original Primary Outcome Measures (submitted: October 28, 2017)

• To assess the distribution volume ratio (DVR) [ Time Frame: end of study ]
• To assess the percent BOLD signal change after MP (oral and iv) [ Time Frame: end of study ]
• To assess the percent DVR change after MP (oral and iv) [ Time Frame: end study ]
• To assess the temporal correlation between BOLD(t) and DVR(t) [ Time Frame: end of study ]

Current Secondary Outcome Measures (submitted: July 25, 2020)

• Pupil size, Eye Blinks, HR, BP, Respiration Rate [ Time Frame: end of study ]
  To assess the correlation between BOLD(t) and behavioral measures (pupil size, eye blinks, heart rate, blood pressure, and respiration rate).
• Heart rate, BP, Respiration Rate [ Time Frame: end of study ]
  To assess the correlation between DVR(t) and behavioral measures (heart rate, BP, and respiration rate).

Original Secondary Outcome Measures (submitted: October 28, 2017)

• To assess the correlation between DVR(t) and behavioral measures (pupil size, eye blinks, heart rate, BP, and respiration rate). [ Time Frame: end of study ]
• To assess the correlation between BOLD(t) and behavioral measures (pupil size, eye blinks, heart rate, blood pressure, and respiration rate). [ Time Frame: end of study ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dopaminergic Modulation of Brain Activation Using Simultaneous PET/Pharmacological MRI
• Official Title: Dopaminergic Modulation of Brain Activation Using Simultaneous PET/Pharmacological MRI

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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Basic Science
• Condition: Normal Physiology

Intervention

• Drug: Oral Methylphenidate followed by IV placebo
  Oral MP (60 mg) will be given 30 minutes prior to bolus [11C]raclopride injection followed by iv placebo (PL) given 30 minutes post bolus injection of [11C]raclopride.
• Drug: Oral placebo followed by IV Methylphenidate
  Oral PL will be given 30 minutes prior to bolus [11C]raclopride injection followed by iv MP (0.25 mg/kg) given 30 minutes post bolus injection of [11C]raclopride.
• Drug: Oral Placebo followed by IV Placebo
  Oral PL will be given 30 minutes prior to bolus [11C]raclopride injection followed by iv PL given 30 minutes post bolus injection of [11C]raclopride.

Study Arms

• Active Comparator: 1:Oral MP- IV PL
  Oral Methylphenidate /IV Placebo
  Intervention: Drug: Oral Methylphenidate followed by IV placebo
• Active Comparator: 2 Oral PL/IV MP
  Oral Placebo/IV Methylphenidate
  Intervention: Drug: Oral placebo followed by IV Methylphenidate
• Placebo Comparator: 3: Oral PL/IV PL
  Oral Placebo/IV Placebo
  Intervention: Drug: Oral Placebo followed by IV Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 9, 2024): 25
• Original Estimated Enrollment (submitted: October 28, 2017): 40
• Actual Study Completion Date: February 8, 2024
• Actual Primary Completion Date: December 13, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

• 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. 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/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).
• 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03326245
• Other Study ID Numbers: 170178; 17-AA-0178
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: .Data is analyzed by subject group and not on an individual basis.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Dardo G Tomasi, Ph.D.; National Institute on Alcohol Abuse and Alcoholism (NIAAA)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: October 27, 2023