Dopaminergic Modulation of Brain Activation Using Simultaneous PET/Pharmacological MRI

Phase 1

Completed

Conditions: Normal Physiology

Interventions: Drug: Oral Placebo
Drug: Methylphenidate Pill
Drug: Intravenous Placebo
Drug: Intravenous methylphenidate

Registration Number: NCT03326245

Lead Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm A: Oral methylphenidate followed by intravenous placebo	Intravenous Placebo	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 B: Oral placebo followed by intravenous methylphenidate	Oral Placebo	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 B: Oral placebo followed by intravenous methylphenidate	Intravenous methylphenidate	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 C: Oral placebo followed by intravenous placebo	Oral Placebo	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.
Arm C: Oral placebo followed by intravenous placebo	Intravenous Placebo	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.
Arm A: Oral methylphenidate followed by intravenous placebo	Methylphenidate Pill	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.

Primary Outcome Measures

Name	Time	Method
The Standardized Uptake Value Ratio (SUVR) for [11C]Raclopride in Putamen	60 min after [11C]raclopride injection	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.
The Temporal Correlation Between BOLD(t) and SUVR(t) Change	From 0 to 90 minutes after [11C]raclopride injection	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.
Percent BOLD Signal Change in the Anterior Cingulum	From 0 to 90 minutes after [11C]raclopride injection	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.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (1): National Institutes of Health Clinical Center
🇺🇸
Bethesda, Maryland, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States