The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats

Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p = 0.02) and rats (F(1,5)26.04, p = 0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p = 0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t = 2.6(16) p = 0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB’s hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB’s ability to enhance cerebral metabolism might be limited

template volume data

Volumetric data derived from the RESILIENT longitudinal MRI stud

Age-Specific Adult Rat Brain MRI Templates and Tissue Probability Maps

Age-specific resources in human MRI mitigate processing biases that arise from structural changes across the lifespan. There are fewer age-specific resources for preclinical imaging, and they only represent developmental periods rather than adulthood. Since rats recapitulate many facets of human aging, it was hypothesized that brain volume and each tissue's relative contribution to total brain volume would change with age in the adult rat. Data from a longitudinal study of rats at 3, 5, 11, and 17 months old were used to test this hypothesis. Tissue volume was estimated from high resolution structural images using a priori information from tissue probability maps. However, existing tissue probability maps generated inaccurate gray matter probabilities in subcortical structures, particularly the thalamus. To address this issue, gray matter, white matter, and CSF tissue probability maps were generated by combining anatomical and signal intensity information. The effects of age on volumetric estimations were then assessed with mixed-effects models. Results showed that herein estimation of gray matter volumes better matched histological evidence, as compared to existing resources. All tissue volumes increased with age, and the tissue proportions relative to total brain volume varied across adulthood. Consequently, a set of rat brain templates and tissue probability maps from across the adult lifespan is released to expand the preclinical MRI community's fundamental resources

Non-Invasive measurement of the cerebral metabolic rate of oxygen using MRI in rodents

Malfunctions of oxygen metabolism are suspected to play a key role in a number of neurological and psychiatric disorders, but this hypothesis cannot be properly investigated without an in-vivo non-invasive measurement of brain oxygen consumption. We present a new way to measure the Cerebral Metabolic Rate of Oxygen (CMRO (2)) by combining two existing magnetic resonance imaging techniques, namely arterial spin-labelling and oxygen extraction fraction mapping. This method was validated by imaging rats under different anaesthetic regimes and was strongly correlated to glucose consumption measured by autoradiography