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The living brain teems with small molecules: These are metabolites that, among other things, transmit neuronal messages, supply energy and synthesize membranes. But when it comes to monitoring the workings of the living brain, the prime noninvasive methods available for this purpose – magnetic resonance imaging (MRI) and related magnetic resonance technologies – provide information only about the water in which these vital molecules are dissolved, not about the metabolites themselves. As reported recently in Nature Communications, Weizmann Institute researchers, in collaboration with scientists from the National High Magnetic Field Laboratory in Florida, have now devised a sophisticated magnetic resonance technique for directly monitoring metabolites.
MRI technologies enable the imaging of living tissue by placing it inside a static magnetic field and exciting the tissue’s atoms with a weak electromagnetic wave in the radiofrequency range. This excitation causes the atoms to oscillate, and magnetic resonance equipment measures the oscillation frequencies for the various atoms. MRI is normally employed to monitor hydrogen, ubiquitous in all living tissue and a main component of water. But the availability of metabolites is about 10,000 times lower than that of water – their magnetic resonance signals are drowned out by the water when standard MRI is applied.
In a new study performed on rats, researchers successfully applied advanced magnetic resonance methods to measure several brain metabolites whose levels are known to be altered by stroke. The findings, obtained immediately after the rats underwent a stroke as well as during their recovery, matched patterns known from such invasive studies as the sampling of brain fluids. Furthermore, the research revealed the microarchitecture of brain structures housing the metabolites in healthy brains and in the areas affected by stroke. These microscopic structures were significantly distorted after the stroke, evidently due to swelling and lack of oxygen.
A key factor that made the study possible was the use of an extremely strong magnet of 21 tesla, presently available only for research on rodents; this far exceeds the sensitivity of current clinical MRI systems, which operate at 3 tesla. Another crucial factor was the magnetic resonance approach itself: The scientists performed the scanning using a new sequence of radiofrequency pulses that excited the metabolites’ hydrogen atoms but left the water’s hydrogen practically undisturbed. Thus they were able to observe the weak signals emitted by the metabolites while avoiding the much stronger signal emitted by the water. In addition, the method allowed the scientists to exploit the fact that with this selective excitation, metabolites revert from the excited state to equilibrium much faster than does water’s hydrogen, which also facilitated signal collection. The study was performed by Prof. Lucio Frydman and Drs. Noam Shemesh and Jean-Nicolas Dumez of the Weizmann Institute’s Chemical Physics Department, and Prof. Samuel Grant, Dr. Jens Rosenberg and Jose Muniz of the National High Magnetic Field Laboratory in Tallahassee, where the 21 tesla system is housed.
This research opens up new possibilities for studying the living brain by monitoring its metabolites. Such monitoring may in the future be developed into a safe, noninvasive method for diagnosing stroke, as well as for detecting early signs of various brain disorders in which metabolite levels are altered, among them Parkinson’s disease, schizophrenia and Alzheimer’s disease.
Prof. Lucio Frydman's research is supported by the Helen and Martin Kimmel Institute for Magnetic Resonance Research, which he heads; the Helen and Martin Kimmel Award for Innovative Investigation; the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; the Mary Ralph Designated Philanthropic Fund of the Jewish Community Endowment Fund; Gary and Katy Leff, Calabasas, CA; Paul and Tina Gardner, Austin, TX; and the European Research Council.
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