Effects of USP Methylene Blue on Cognitive and fMRI Brain Activity

Sponsor

The University of Texas Health Science Center at San Antonio (Other)

Overall Status

Completed

CT.gov ID

NCT01836094

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate whether low-dose USP methylene blue (MB) will: i) improve short-term memory retention in a delayed match-to-sample task, ii) reduce reaction time in a psychomotor vigilance test, and iii) enhance responses to a visual-motor task as measured by functional magnetic resonance imaging (fMRI).

A single low-dose MB or placebo will be orally administered to self-declared healthy adults using double-blind study design. Non-invasive fMRI data will be acquired before and after MB administration in the same subjects. Each study will take 2-3 hours, inclusive of an hour break in between.

Condition or Disease	Intervention/Treatment	Phase
Brain Activity	Drug: Methylene Blue (USP grade, 280mg oral) Drug: Placebo	Early Phase 1

Detailed Description

Self-declared healthy adult volunteers will be studied using a double-blind, placebo-controlled design. After informed consent and familiarity with the tasks and the MRI environment, the subject will enter an MRI scanner and perform the following 3 tasks:

Delayed match-to-sample task: The subject views an object for a few seconds. After a few (variable) seconds, the subject is presented with two patterns and the subject needs to press the left or right button based on whether the picture on the left or the right is the same as the previous picture. The correct and incorrect answers are recorded. A few of these trials will be cycled, lasting about 5-10 mins.

Psychomotor vigilance test: The subject will receive a visual cue to press a button as fast as possible. The reaction time is recorded. A false start is when the subject presses before the visual cue and that trial is not counted. The subject is instructed to avoid a false start. A few of these trials will be cycled, lasting about 5-10 mins.

Visual-motor task: The subject is instructed to tap his/her 4 fingers against the thumb every second and cycle through the 4 fingers, in synchrony with an alternating visual checkerboard patterns. A few of these trials will be cycled, lasting about 5-10 mins.

For calibration of the fMRI signal, fMRI data will also be acquired during a brief (3-5 mins) inhalation of 5% CO2 in air.

fMRI measurements will be made before intervention. The subject comes out of the scanner, orally ingests the USP MB or placebo, and waits for an hour (break). The same measurements will then be repeated.

fMRI data acquisition: The MRI pulse sequences include standard and non-invasive anatomical MRI for co-registration, blood flow and blood-oxygen-level dependent (BOLD) fMRI. fMRI will image changes in regional brain activity associated with these tasks.

In addition, one week after the fMRI study, the subject will be emailed a short questionnaire (which takes a few minutes to answer) and the responses can be returned via email.

Data analysis: Standard fMRI analysis will be analyzed using established fMRI software. Statistical parametric analysis will be performed to generate activation maps. Task-evoked changes in brain activities will be analyzed and contrasted between placebo and MB conditions in the same subjects. Paired t-test will be used for group comparison with P < 0.05 (with bonferroni correction) considered statistically significant.

Expected results: The investigators predict that, compared to placebo, MB will: i) improve short-term memory retention in a delayed match-to-sample task by memory performance and enhanced fMRI responses in the prefrontal cortex-hippocampus, ii) reduce reaction time in a psychomotor vigilance test and enhanced fMRI responses within a cortical sustained attention network and the motor systems, and iii) enhance responses in the visual and motor cortices.

Power analysis: Sample sizes were calculated for a power of 80%, alpha = 0.05 to detect statistical difference between MB and placebo. The investigators estimate they will need 40 subjects (complete studies) and thus will recruit 50 subjects to account for potential failed studies.

Study Design

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

Beneficial Effects of Methylene Blue on Human Cognitive and fMRI Measures

Study Start Date :

Aug 1, 2013

Actual Primary Completion Date :

Mar 1, 2016

Actual Study Completion Date :

Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methylene Blue Methylene Blue, 280mg, oral, one time	Drug: Methylene Blue (USP grade, 280mg oral) Other Names: USP Methylene Blue, Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate
Placebo Comparator: Placebo FD&C Blue No. 2 (food dye), oral, one time	Drug: Placebo oral, one time Other Names: FD&C Blue No. 2 (food dye)

Arm

Intervention/Treatment

Experimental: Methylene Blue

Methylene Blue, 280mg, oral, one time

Drug: Methylene Blue (USP grade, 280mg oral)

Other Names:

USP Methylene Blue, Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate

Placebo Comparator: Placebo

FD&C Blue No. 2 (food dye), oral, one time

Drug: Placebo

oral, one time

Other Names:

FD&C Blue No. 2 (food dye)

Outcome Measures

Primary Outcome Measures

Improvement in reaction time assessed by fMRI measurements and PVT measurements [1 hour]
fMRI will be assessed using standard fMRI analysis tools. Psychomotor-Vigilance-Test (PVT) measurements will be made using a computer program written in Psychology Experiment Building Language (PBL).
Improvement in memory assessed by fMRI measurements and DMS measurements [1 hour]
fMRI will be assessed using standard fMRI analysis tools. Delayed-match-to-sample task (DMS) measurements will be made using a computer program written in Psychology Experiment Building Language (PBL).

Secondary Outcome Measures

Enhanced fMRI responses to visual-motor task [1-2 hours]
fMRI will be assessed using standard fMRI analysis tools.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Age 18 - 65 years, self declared healthy individuals
English speaker and be able to give consent

Exclusion Criteria:

Contraindication for MRI (pacemaker, metal implants, etc.)
Claustrophobia
Pregnant (child-bearing age females will be tested to exclude pregnancy onsite)
Breast-feeding
A history of hypersensitivity or allergy to methylene blue, glucose-6-phosphate dehydrogenase deficiency (determined via questionnaire)
Neurological, mental, or cardiovascular disorders
Liver, kidney disorders, kidney or liver transplant, hypertension, diabetes, etc.
Known hypersensitivity to thiazide diuretics and phenothiazines
A history of a psychotic disorder or panic disorder, violent or suicidal behavior, psychiatric institutionalization or imprisonment
Any other condition, which in the opinion of the investigator, would put the participant at risk and warrant exclusion from the study
Methemoglobinemia
On any psychiatric serotonergic antidepressant medication or drugs of abuse currently or within the last 5 weeks
History of panic attack
Color Blindness