Magnetic resonance without magnets: explained

Have you ever done MRI? If yes, you probably remember, it is not the most pleasant experience. MRI is claustrophobic, loud, and takes a long time. The main reason for these problems — high magnetic fields. Would it be cool to avoid them? Why can’t we simply do MRI without magnetic fields?

It turns out, we can do it though it is not that simple…

To understand why high magnetic fields are needed to obtain magnetic resonance images, we need to understand the principles of signal detection and the concept of polarization.

Some atomic nuclei possess a property called spin and, therefore, produce magnetic fields. These nuclei can simply be visualized as tiny magnets (magnetic dipoles) swirling in space as their hosts — molecules — move, rotate or vibrate depending on the physical state of the chemical system they comprise (solid, liquid or gas).

In the absence of external fields, nuclear spin orientations are random:

By placing the spins in high magnetic fields, one can align them in the same direction, creating “polarization”:

The level to which spins are polarized in the picture above is extremely exaggerated. In reality, even in the very high magnetic fields of modern magnetic resonance spectrometers and imaging scanners (thousands of times higher than the Earth’s magnetic field), nuclear spin polarization is only a fraction of percent. Complete (100%) polarization is also possible. However, instead of placing spins in high fields, it is practically more feasible to use a different approach. Physicists and chemists came up with several creative techniques to create extremely high polarization or hyperpolarization. Techniques based on chemical reactions (such as parahydrogen-induced polarization) are my favorite ones since they don’t require magnetic fields at all (in reality, polarization in such techniques can still be magnetic-field-dependent but the requirements are very modest).

Now about detection. Nuclear magnetism can be detected in several ways. I will talk about two ways and both of them are named after a brilliant physicist Michael Faraday.

The first detection technique is the so-called inductive detection. If spins are polarized and brought to the magnetic field perpendicular to the polarization axis, collective nuclear magnetization will start oscillating about the field axis. This phenomenon is called Larmor precession and it is a general result of classical physics (no quantum mechanics is necessary to explain it but quantum mechanics brings more fun). Oscillating magnetization can be picked up by a coil (solenoid) and a voltage across the coil terminals (electromotive force) will be generated according to Faraday’s law of induction:

Collective nuclear spin magnetization (M) is rotating about the magnetic field (B0). When a pre-polarized (or, simply speaking, pre-magnetized) sample is placed in such a field, M starts oscillating and its z-component generates an oscillating voltage across the coil’s terminals according to the Faraday’s law.

The problem is that it is really hard to construct magnets that produce high magnetic fields. Moreover, these fields need to be very uniform to be suitable for magnetic resonance purposes. This is why bores of MRI scanners are usually small – this way engineers achieve higher magnetic field homogeneity over the active volume.

The conventional logic of MRI engineers is straightforward: by using higher magnetic fields (1) we achieve higher nuclear spin polarization (indeed, polarization scales linearly with the applied field B0) and (2) we increase sensitivity of the detection (the voltage generated in the coil by Faraday’s law is linearly proportional to the oscillation frequency which, in turn, proportional to B0). Therefore, conventional MRI signal scales as a square of the magnetic field. Higher the field is — bigger the magnet should be, and we already reached the limits of our engineering capabilities to make the highest magnetic fields that are stable and uniform.

Now imagine that we already have high polarization produced without magnetic fields, for example, via chemical reactions mentioned above. Therefore, the signal is only linearly proportional to the magnetic field strength and even low magnetic fields can be used to produce high-quality images.

Recently my students and I played with MRI at the Earth’s magnetic field (compare 50 micro-Tesla vs. several Tesla of conventional MRI scanners). In our experiments, we simply bubbled a gas through a solution containing the required ingredients and picked up the signal by a coil:

Bubbling para-H2 gas through a solution containing a “polarizable” substrate and a SABRE catalyst.

The gas that we used is parahydrogen (para-H2) and the enhanced nuclear polarization in solution is the result of Signal Amplification By Reversible Exchange (SABRE) effect. This effect is a remarkable consequence of the interplay between chemical kinetics and nuclear spin dynamics. Unfortunately, explaining it here, in this post, would require many more words and even some math 🙂 But the main point is simple: bubbling the gas through the solution results in high nuclear polarization and, therefore, high MRI contrast. Without bubbling the gas, magnetic nuclei are oriented randomly and the signal is too low to be detected.

MRI of a SABRE solution at the Earth’s magnetic field (left) when para-H2 gas is bubbled and (middle) when the gas supply is ceased. (Right) Proton Nuclear Magnetic Resonance (NMR) spectrum of the solution at the Earth’s magnetic field.

This idea of avoiding magnetic fields can be extended even further. Indeed, if we don’t need a magnetic field to generate polarization, can we detect nuclear spin signals completely without magnets? This somewhat weird idea (magnetic resonance without magnets) is, in fact, one of the most outstanding achievements in magnetic resonance of the last decade. It was pioneered by chemists and physicists from UC Berkeley (laboratories of Alex Pines and Dmitry Budker).

It turns out that very weak magnetic signals can be detected by atomic magnetometers. These magnetometers use vapor cells, glass containers filled with the vapor of alkali metal. Atoms of alkali metals have unpaired valence electrons. Since electrons are tiny magnets in the same way as their nuclear brothers, they can also be polarized, this time by lasers. Properties of a laser beam passing through such polarized “electronic gas” can be modulated if electrons are subjected to additional magnetic fields. This is called the Faraday effect and it is a second way of detecting magnetic resonance signals. In a nutshell, electrons “feel” the magnetic fields around them in a very sensitive way, even if these fields are generated by nuclear spins from a sample placed on top of a vapor cell:

Magnetization (M) generated in a sample can be detected by atomic magnetometers. The most sensitive magnetometers operate at a near-zero magnetic field. Signal can be detected by lasers due to the Faraday effect using a variety of polarimetry schemes.

The end result of this signal detection scheme is the same as before – the voltage is generated and picked up, this time by a photodetector. If magnetic fields coming from the sample are time-dependent, the voltage is time-dependent as well and it can be converted into a spectrum containing useful chemical information about the sample.

You might wonder where this all can be applied? Well, it is worth mentioning Faraday here again:

I personally feel that MRI without magnets is not only possible but necessary. However, it will obviously not replace the conventional approach but will rather complement it. One may imagine sensitive magnetometers and Earth’s-field MRI applied to study chemicals at a large scale, to investigate processes taking place inside big industrial chemical reactors. Indeed, the Earth is the best magnet for these purposes – it is extremely homogeneous on the scale that we need. Nullifying magnetic fields (to produce zero field) is another option – remarkably, the sensitivity of atomic magnetometers is maximized at the near-zero-field conditions. It is hard to predict the direction that future will take but one thing is clear – magnetic resonance is entering a new era. So you better stay tuned! 😉

Further reading

https://chemrxiv.org/articles/Zero-Field_Nuclear_Magnetic_Resonance_of_Chemically_Exchanging_Systems/7658372

https://aip.scitation.org/doi/abs/10.1063/1.5003347

https://www.nature.com/articles/nphys1986

https://onlinelibrary.wiley.com/doi/abs/10.1002/cphc.201402607

https://pubs.acs.org/doi/abs/10.1021/ac501638p

https://www.sciencedirect.com/science/article/abs/pii/S1090780717301659

We are, simply, chemical reactions

I have recently read this article and it was well discussed how scientists keep discovering new interesting and important facts about our gastrointestinal tract and its effect on our wellbeing (including decision making and brain function).

For example, it has been shown that if people eat more galactooligosaccharide, the fraction of bacteria Lactobacillus and Bifidobacteria in the gut increases among all other strains (because metabolism of these bacteria takes advantage of the excess of this chemical, a known prebiotic). At the same time, these particular strains of bacteria have been shown to produce certain neurotransmitters — chemicals that participate in our brain functioning (because neurotransmitters are responsible for the transmission of electrical signals between neurons). It is indeed possible that by eating certain types of food you can overproduce certain neurotransmitters and, therefore, influence your brain functioning — through bacteria in the gut (Figure 1).

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Figure 1. Feeding healthy volunteers with galactooligosaccharide resulted in the increased population of Lactobacillus and Bifidobacteria in the gut which, in turn, resulted in overproduction of neurotransmitters that affect anxiety, including one called brain-derived neurotrophic factor [1].

What is even cooler, some bacteria have shown to affect people’s mood (possibly, by increasing production of “happiness hormones”, in other words, chemicals responsible for our social behavior). This is reasonable because happy people are more social which leads to a big evolutionary advance for these bacteria: they would obviously tend to spread better between social humans than between loners. Interesting, isn’t it?

Let’s now think about it in an evolutionary context. Do bacteria in the gut understand that they change the social behavior of their hosts? The answer is – NO. They not only don’t know anything about social behavior, but they also don’t know that they have a host and even that they exist! Bacteria are simply self-sustaining chemical reactions capable of changing (mutating) their chemical dynamics. It is not that bacteria have goals to survive, they simply occur. One random mutation in their genome led to the overexpression of a random chemical which, by a myriad of other complicated chemical transformations led to the increase of a random neurotransmitter which, by accident, tended to affect social behavior of their hosts. Now, the bacteria have started to spread faster and still spread “happily” because these chemical dynamics help them to exist or, simply, to occur.

We, humans, are chemical reactions too. All hopes and dreams in our brains are interactions between atoms, molecules and their collections. We just tend to occur because it is evolutionary logical. Our mood is chemistry too: serotonin is happiness, dopamine is pleasure, noradrenaline is concentration (Figure 2).

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Figure 2. The structures of neurotransmitters and their common effects on the mood, concentration, and learning.

So, if all of this is chemistry, then how to study this? Are there techniques that would allow us to investigate gut microbiome and its effect on the brain non-invasively and in real time?

I believe the answer is yes. Non-invasive techniques like NMR and MRI will soon be able to help to answer important questions about gut metabolism with hyperpolarization being one of the main tools to achieve this. The main challenge – fast decay of polarization – will be overcome by using nuclear states that can preserve their “memory” on a timescale of hours. Remarkably, there are already reports on the long-lived hyperpolarized nuclear spin states [2-4]! Long-live the gut! 😉

[1] “When Gut Bacteria Change Brain Function” bDavid Kohn.

[2] https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201405063

[3] https://pubs.acs.org/doi/abs/10.1021/acs.jpclett.7b00987

[4] https://www.sciencedirect.com/science/article/abs/pii/S1090780717300216

My “Dream Research” Project

If I was asked to identify the most challenging biological question, I would answer immediately. What is the nature of memory and thought? This question always fascinated me as a child. For a long time, I thought only biologists can figure that out. It took me 10 years deeply studying physics and chemistry, becoming a specialist in nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI), to realize that actually now we are close to start answering the question which captivated my childish mind.

 

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Metabolic Metro Map. The image is taken from Wikipedia.

 

With all its complexity, the end result of the genetic machinery is to affect the chemistry of the body. Small molecules, metabolites, serve as fingerprints of what is happening inside us. Studying metabolites is almost like looking at someone’s apartment and coming up with a story of their recent lives: we can make guesses about a lifestyle based on what we see! And the chemistry of thinking is not an exception – our thought processes are accompanied by myriads of chemical transformations, and leftover metabolites can tell us about the process behind them.

Studying metabolites is almost like looking at someone’s apartment and coming up with a story of their recent lives: we can make guesses about a lifestyle based on what we see!

Routinely, metabolites are measured through analytical techniques like NMR and mass spectrometry (MS). But a new astonishing era is emerging. With new sensitivity enhancement techniques (signals can be increased by more than 20,000 times [1-4]), MR imaging will become a new tool to study metabolism in vivo and will move beyond morphology onto a platform to visualize molecules. Being fundamentally a quantum mechanical technique, the full potential of MRI is yet to be discovered.

I see my “dream research” project as the development of a new experimental MRI-NMR/MS platform to study metabolomics of memory and thought in living creatures. By developing novel MRI pulse sequences (which will take into account quantum-mechanical nature of molecules) and by applying state-of-the-art signal enhancement techniques, we will be able to “light up” the regions of the brain to study chemistry in them with an unprecedented level of accuracy. I believe that once all new methodologies available today are combined, it will become possible to create functional MRI for metabolomics – a tool to study instant chemical changes in the brain associated with memory and thinking. This will not only revisit the known biochemical processes at a new quantitative level, it will allow unraveling unexpected secrets of metabolism. And it is not only a fun thing to do — understanding the biochemical reasons for making decisions will bring us much closer to a society in which everyone truly enjoys living.

 

[1] J. H. Ardenkjær-Larsen et al. Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proc. Nat. Acad. Sci., 2003, 100 (18), 10158-10163.

[2] R. W. Adams et al. Reversible Interactions with parahydrogen Enhance NMR Sensitivity by Polarization Transfer. Science, 2009, 323 (5922), 1708-1711.

[3] D. A. Barskiy et al. Over 20% 15N Hyperpolarization in Under One Minute for Metronidazole, an Antibiotic and Hypoxia Probe. J. Am. Chem. Soc., 2016, 138 (26), 8080–8083.

[4] D. A. Barskiy et al. NMR Hyperpolarization Techniques of Gases. Chem. Eur. J., 2017, 23 (4), 725-751.