The Monro-Kellie doctrine states that the sum of the contents of the intracranial cavity is constant, and consequently dynamics of blood and cerebrospinal fluid (CSF) volumes should be in an anti-correlation relationship. This phenomenon helped to explain many abnormalities in intracranial hypotension and CSF depletion. We aimed to validate the same phenomenon in mice during a blood pressure (BP) lowering test. Eight 2–3-month-old C57/Bl6N (Charles River) female mice were used in this study. We used both nicardipine hydrochloride and sodium nitroprusside (SNP) infusion into the femoral vein to lower the BP. A multi-wavelength NIRS (685, 830, and 980 nm) measuring hemoglobin and water concentrations, sampled at 800 Hz, was used. The fiber probes for the light source and detector were inserted into the ear canals and positioned towards the brain, giving a distance of approximately 1 cm. Following the Monro-Kellie doctrine, the blood volume, i.e., total hemoglobin (HbT), and CSF volume should be in an anti-correlation relationship. Our experiments showed that concentration changes of total hemoglobin (HbT) and water, are in anti-correlation with correlation coefficients of -0.991 ± 0.007.
Enhancing brain fluid movement across blood brain barrier (BBB) has been recognized as a potential treatment of neurodegenerative diseases. Moreover, BBB opening is of high interest also in brain drug delivery in the treatment of brain tumors/cancers. However, efficient therapies which are based on BBB opening are still limited because of insufficient understanding of mechanisms and safety issues. Currently, there are few promising methodologically diverse BBB opening approaches. In this paper, we use functional near-infrared spectroscopy (fNIRS) for the first time for monitoring cerebral hemoglobin and water concentration changes during BBB opening in mouse brain by using two different techniques: intra-arterial mannitol infusion (IAM) and focused ultrasound (FUS). Both of these BBB opening techniques are already in clinical use but their hemo- and hydrodynamic implications have not been investigated from comparative aspect. Two fibre detectors were attached on both sides of the mouse brain and the source fibre was attached on middle of forehead. Further, by using a combination of three wavelengths 690nm, 830nm and 980nm, that have sufficient light penetration in the mouse brain, we can show average dynamics of hemoglobin and water in the whole brain, synchronized with BBB opening. To validate the level of BBB opening we used Evans blue dye and show its accumulation in the brain parenchyma tissue with the corresponding fNIRS responses.
Monitoring blood-brain barrier (BBB) opening is of great interest in terms of brain drug delivery in the treatment of brain lymphoma and maybe in the future in other diseases like dementia. A method involving BBB disruption (BBBD) by mannitol infusion has been developed in University of Portland, USA, and then exploited in Oulu University Hospital in treatment of primary CSN lymphoma. Proper opening of the BBB is crucial for the treatment, yet there are no methods available for its real-time clinical monitoring. Recently, we presented a combined method using direct-current electroencephalography (DC-EEG) and near-infrared spectroscopy (NIRS) for monitoring BBBD in human. Carotid artery mannitol infusion generated a strongly lateralized DC-EEG response and in NIRS a prolonged increase in the oxy/deoxyhemoglobin ratio.
This study explores further BBBD, by focusing on monitoring its cardiovascular effects, when measured in human and mouse. For this, we used photoplethysmography (PPG) and opto-electro-mechanical sensors to gather the signals in human and mouse. Mannitol infusion in human causes strong fluctuations in blood pressure, heart rate and PPG signals, and here we discuss how the acquired signals in mouse model compares to human data.
In addition, we present our scale-free monitoring concept that enables monitoring physiological signals similarly when performing experiments in mouse and human neuroimaging setups. By combining microscopic and macroscopic imaging in mouse setup enables us to study correlations between mechanistic cellular data and clinical functional data. Further, this allows us to validate and optimize macroscopic sensing and imaging techniques aimed to be used in human imaging.
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