Manganese Dynamics in Mouse Brain After Systemic MnCl2 Administration for Activation-Induced Manganese-Enhanced MRI.

Activation-induced manganese-enhanced MRI (AIM-MRI) is an attractive tool for non-invasively mapping whole brain activities. Manganese ions (Mn2+) enter and accumulate in active neurons via calcium channels. Mn2+ shortens the longitudinal relaxation time (T1) of H+, and the longitudinal relaxation rate R1 (1/T1) is proportional to Mn2+ concentration. Thus, AIM-MRI can map neural activities throughout the brain by assessing the R1 map. However, AIM-MRI is still not widely used, partially due to insufficient information regarding Mn2+ dynamics in the brain. To resolve this issue, we conducted a longitudinal study looking at manganese dynamics after systemic administration of MnCl2 by AIM-MRI with quantitative analysis. In the ventricle, Mn2+ increased rapidly within 1 h, remained high for 3 h, and returned to near control levels by 24 h after administration. Microdialysis showed that extracellular Mn returned to control levels by 4 h after administration, indicating a high concentration of extracellular Mn2+ lasts at least about 3 h after administration. In the brain parenchyma, Mn2+ increased slowly, peaked 24-48 h after administration, and returned to control level by 5 days after a single administration and by 2 weeks after a double administration with a 24-h interval. These time courses suggest that AIM-MRI records neural activity 1-3 h after MnCl2 administration, an appropriate timing of the MRI scan is in the range of 24-48 h following systemic administration, and at least an interval of 5 days or a couple of weeks for single or double administrations, respectively, is needed for a repeat AIM-MRI experiment.

Visualization of Brain Activity in a Neuropathic Pain Model Using Quantitative Activity-Dependent Manganese Magnetic Resonance Imaging.

Human brain imaging studies have revealed several regions that are activated in patients with chronic pain. In rodent brains, functional changes due to chronic pain have not been fully elucidated, as brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography (PET) require the use of anesthesia to suppress movement. Consequently, conclusions derived from existing imaging studies in rodents may not accurately reflect brain activity under awake conditions. In this study, we used quantitative activation-induced manganese-enhanced magnetic resonance imaging to directly capture the previous brain activity of awake mice. We also observed and quantified the brain activity of the spared nerve injury (SNI) neuropathic pain model during awake conditions. SNI-operated mice exhibited a robust decrease of mechanical nociceptive threshold 14 days after nerve injury. Imaging on SNI-operated mice revealed increased neural activity in the limbic system and secondary somatosensory, sensory-motor, piriform, and insular cortex. We present the first study demonstrating a direct measurement of awake neural activity in a neuropathic pain mouse model.