One oral dose of methylene blue results in an increased MRI-based response in brain areas that control short-term memory and attention, according to a new study.
Methylene blue, also known as methylthioninium chloride, is used to treat methemoglobinemia, a blood disorder in which oxygen is unable to release effectively to body tissues, and as a surgical stain.
Animal studies have shown a single low dose of methylene blue enhances long-term contextual memory, the conscious recall of the source and circumstances of a specific memory, as well as extinction memory, a process in which a conditioned response from stimuli gradually diminishes over time.
Study author Timothy Q. Duong, Ph.D., from the University of Texas Health Science Center at San Antonio, Texas, said:
“Although the memory-enhancing effects of methylene blue were shown in rodents in the 1970s, the underlying neuronal changes in the brain responsible for memory improvement and the effects of methylene blue on short-term memory and sustained-attention tasks have not been investigated. Our team decided to conduct the first multi-modal MRI study of methylene blue in humans."
Methylene blue has been described as the first fully synthetic drug used in medicine.
Its use in the treatment of malaria was pioneered by Paul Guttmann and Paul Ehrlich in 1891. During this period before the first World War, researchers like Ehrlich believed that drugs and dyes worked in the same way, by preferentially staining pathogens and possibly harming them.
Methylthioninium chloride has been used as a placebo; physicians would tell their patients to expect their urine to change color and view this as a sign that their condition had improved. Conversely, the same side effect makes methylene blue challenging to test in traditional placebo-controlled clinical studies.
In this study, twenty-six healthy participants, between the ages of 22 and 62, were enrolled in a double-blinded, randomized, placebo-controlled clinical trial to measure the effects of methylene blue on the human brain during working-memory and sustained-attention tasks. This study was approved by the local ethical committee.
The participants underwent functional MRI (fMRI) before and one hour after low-dose methylene blue or placebo administration to evaluate the potential effects of methylene blue on cerebrovascular reactivity during tasks. Mean cerebral blood flow was measured pre- and post-intervention.
Short Term Memory Improvements
The results showed methylthioninium chloride increased response in the bilateral insular cortex, an area deep within the brain associated with emotional responses, during a task that measured reaction time to a visual stimulus.
The fMRI results also showed an increased response during short-term memory tasks involving the brain’s prefrontal cortex, which controls processing of memories, the parietal lobe, primarily associated with the processing of sensory information, and the occipital cortex, the visual processing center of the brain.
In addition, methylene blue was associated with a 7 percent increase in correct responses during memory retrieval.
The findings suggest that methylene blue can regulate certain brain networks related to sustained attention and short-term memory after a single oral low dose.
“This work certainly provides a foundation for future trials of methylene blue in healthy aging, cognitive impairment, dementia and other conditions that might benefit from drug-induced memory enhancement,” Dr. Duong said.
Pavel Rodriguez, Wei Zhou, Douglas W. Barrett, Wilson Altmeyer, Juan E. Gutierrez, Jinqi Li, Jack L. Lancaster, Francisco Gonzalez-Lima, Timothy Q. Duong Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain Radiology, 2016; 152893 DOI: 10.1148/radiol.2016152893
Image: Delayed match-to-sample task. Repeated-measures ANOVA results of the delayed match-to-sample task (colors indicate P values of significant voxels, cluster-based P ? .05; K ? 10) superimposed to a standard brain template.
A, Probability map overlays show positive drug X time interactions in favor of a methylene blue effect in the bilateral inferior frontal gyri during the encoding phase, B, in the right superior frontal gyrus, left middle frontal gyrus, and posterior cerebellum during the maintenance phase, and, C, in the right inferior frontal gyrus and cuneus during the retrieval phase (n = 26, with 24 degrees of freedom). D, Representative blocks from the delayed match-to-sample task show the encoding, maintenance, retrieval, feedback, and rest phases as demarcated by set times.
Credit: Radiological Society of North America