Effects of USP Methylene Blue on Cognitive and fMRI Brain Activity

Brain Activity Clinical Trial

Official title:

Beneficial Effects of Methylene Blue on Human Cognitive and fMRI Measures

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01836094
• Other study ID #: NS 13-208
• Status: Completed
• Phase: Early Phase 1
• First received: April 12, 2013
• Last updated: April 7, 2017
• Start date: August 2013
• Est. completion date: March 2016

Study information

• Verified date: April 2017
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Activity

Intervention

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

• Placebo
oral, one time

Locations

Country	Name	City	State
United States	Research Imaging Institute, The University of Texas Health Science Center at San Antonio	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio

Country where clinical trial is conducted

United States, 

References & Publications (6)

Bruchey AK, Gonzalez-Lima F. Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol. 2008 Jan 1;3(1):72-79. — View Citation

Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004 Sep-Oct;11(5):633-40. — View Citation

Lim J, Wu WC, Wang J, Detre JA, Dinges DF, Rao H. Imaging brain fatigue from sustained mental workload: an ASL perfusion study of the time-on-task effect. Neuroimage. 2010 Feb 15;49(4):3426-35. doi: 10.1016/j.neuroimage.2009.11.020. Epub 2009 Nov 24. — View Citation

Riha PD, Bruchey AK, Echevarria DJ, Gonzalez-Lima F. Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption. Eur J Pharmacol. 2005 Mar 28;511(2-3):151-8. — View Citation

Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA, Goldberg MS, She H, Mao Z, Simpkins JW, Yang SH. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011 May 6;286(18):16504-15. doi: 10.1074/jbc.M110.208447. Epub 2011 Mar 18. — View Citation

Wrubel KM, Riha PD, Maldonado MA, McCollum D, Gonzalez-Lima F. The brain metabolic enhancer methylene blue improves discrimination learning in rats. Pharmacol Biochem Behav. 2007 Apr;86(4):712-7. Epub 2007 Mar 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improvement in reaction time assessed by fMRI measurements and PVT measurements	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).	1 hour
Primary	Improvement in memory assessed by fMRI measurements and DMS measurements	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).	1 hour
Secondary	Enhanced fMRI responses to visual-motor task	fMRI will be assessed using standard fMRI analysis tools.	1-2 hours