As opposed to x-ray and ultrasound scanning devices, MRI uses the body’s innate magnetic properties to produce scans. Magnetic resonance imaging takes advantage of the high abundance of hydrogen nuclei (protons) in soft tissues of the body (which contain water and fat) and the fact that, often, diseases are manifested as an increase in water content as a natural consequence of inflammation.
Every hydrogen proton in the body has a spin and, hence, a small magnetic moment (1). An MRI machine applies a very strong magnetic field across the body to align all the hydrogen protons with the field (2). A radiofrequency pulse is then introduced which forces the hydrogen protons to realign against the magnetic field (3). Once the pulse is removed, the hydrogen protons return to their original alignment and release electromagnetic energy as MR signals which can be detected (4).
Tissue can be analysed and differentiated based on how much energy its constituent hydrogen protons release and how long it takes for them to return to their original alignment (the relaxation time). Since the development of the first MRI scanner, several variants of the underlying principle have emerged to address niche situations.
BOLD fMRI
Blood-oxygen-level dependent functional MRI (BOLD fMRI) works on the principle that an increase in neuronal activity is always accompanied with an increase in oxygenated blood flow in local capillaries as the demand for oxygen increases.
The haemoglobin which delivers oxygen to the activated neurons is paramagnetic when deoxygenated (T-state) but diamagnetic when oxygenated (R-state); this unique magnetic property (caused by its different quaternary structures) results in slightly different electromagnetic emissions from the hydrogen protons within the haemoglobin depending on the level of oxygenation.
The MR signal can be analysed to infer a plethora of information – allowing clinicians to monitor the level of brain activity in a patient suffering from neurodegeneration and enabling researchers to discover the regions of the brain responsible for both instinctive reflexes and complex contemplation.
With its extreme versatility and minimal health risks, MRI arguably forms the heart of modern radiography – however, for certain patients with underlying ailments, the very scanning modality that is renowned for its safety can be deadly.
Safer Contrast Agents
Contrast agents are frequently used in MRI scans to alter the relaxation time of the hydrogen protons through their interaction with strongly paramagnetic gadolinium ions in the dye – this changes the MR signal intensities and increases the contrast of the scan. The gadolinium ions then accumulate in the kidneys for elimination. However, in cases of poor renal function, this can prove to be toxic. Patients with advanced chronic kidney disease, if injected with a typical gadolinium-based contrast agent, are at a significant risk of developing painful, debilitating disorders including contrast-induced nephropathy.
Just last year, a team at Massachusetts General Hospital devised a solution by proposing an alternative, safer manganese-based contrast agent (Mn-PyC3A) which not only produces identical contrast enhancement but is also made of an essential element which poses no risk to human health.
Hyperpolarisation
Within the past decades, although MRI has become indispensable in medical diagnostics, its sensitivity leaves much to be desired. In a typical MRI scan, due to the way that the molecular energies are naturally distributed, the MR signal from only 1 in 200,000 molecules is actually detected. Consequently, vital molecules (including potential cancer biomarkers) remain undetected due to their inherently low concentrations (<1mM) – severely restricting the scope of MRI.
Hyperpolarisation can overcome this sensitivity challenge by skewing the distribution of molecular energies and enabling detection of significantly more molecules. In hyperpolarisation, parahydrogen (polarised H2) or carbon-13 is chemically incorporated into an array of molecules (including glucose, urea, and pyruvate) and injected into the patient as tracers. This can increase the detected MR signal by up to 100,000 fold.
Hyperpolarisation drastically improves the imaging of metabolic activity – which is essential for tumour detection and monitoring. Cancer cells perform rapid glycolysis to obtain energy to fuel growth and division – converting pyruvate into the byproduct lactate in the process. A significant biomarker of aggressive, rapidly-growing tumours is a high lactate concentration. To assess the metabolic activity of a tumour, the patient is injected with carbon-13 enriched pyruvate and the concentration of hyperpolarised lactate produced is measured.
Unlike all other scanning methods, this technique yields information about not only the anatomy of a tumour but also its biochemistry – proving to be invaluable in assessing the efficacy of cancer treatment. Remarkably, within 24 hours of starting a new treatment, hyperpolarised MRI scans can reveal if a tumour is responding.
The figure above shows a prostate tumour before and only 48 hours after starting treatment. The MRI scans in the first row show a slight decrease in tumour size whilst the graphs in the second row (which refer to the detected concentrations of lactate and pyruvate) show that the lactate concentration has plummeted – highlighting the success of the treatment.
This biochemical change is further illustrated in the lactate concentration maps (last row) generated from the hyperpolarised MRI scans.
With MRI hyperpolarisation, clinicians can swiftly identify the ideal treatment for each patient based on the unique metabolism of the tumour – representing a major milestone in advances toward personalised medicine.
The figures quoted in this essay have been meticulously researched and documented. Below is the bibliography for this section of my essay:
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Devlin, Hannah. “Introduction to FMRI.” Nuffield Department of Clinical Neurosciences, University of Oxford, [Last Accessed: 22 Feb] https://www.ndcn.ox.ac.uk/divisions/fmrib/what-is-fmri/introduction-to-fmri
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“Contrast Dye and the Kidneys.” A To Z Health Guide, National Kidney Foundation, https://www.kidney.org/atoz/content/Contrast-Dye-and-Kidneys [Last Accessed: 22 Feb 2019]
Gale, Eric, and Peter Caravan. “Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System.” ACS Chem. Neurosci. 9.3 (2018): 395-397. ACS Publications. Web. [Last Accessed: 22 Feb 2019]
Freeman, Tami. “Medical innovations: A safer MRI contrast agent.” physicsworld: Focus On Biomedical Physics. June 2018: 6. Print. [Last Accessed: 22 Feb 2019]
“What is hyperpolarisation?” Centre for Hyperpolarisation in Magnetic Resonance (CHyM), University of York, https://www.york.ac.uk/chym/hyperpolarisation/ [Last Accessed: 24 Feb 2019]
Miloushev, Vesselin, Kayvan Keshari, and Andrei Holodny. “Hyperpolarization MRI.” Top Magnetic Resonance Imaging 25.1 (2016): 31-37. PMC. Web. [Last Accessed: 03 Mar 2019]
Iali, Wissam, Peter J. Rayner, and Simon B. Duckett. “Using parahydrogen to hyperpolarize amines, amides, carboxylic acids, alcohols, phosphates, and carbonates.” Science Advances 4.1 (2018). American Association for the Advancement of Science. Web. [Last Accessed: 24 Feb 2019]
Ward, Christopher, et al. “Noninvasive Detection of Target Modulation following
Phosphatidylinositol 3-Kinase Inhibition Using Hyperpolarized 13C Magnetic Resonance Spectroscopy.” Cancer Research 70.4 (2010): 1296-1305. American Association for Cancer Research. Web. [Last Accessed: 04 Mar 2019]
“Super-Cool Imaging Technique Identifies Aggressive Tumors.” National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, https://www.nibib.nih.gov/news-events/newsroom/super-cool-imaging-technique identifies-agressive-tumors [Last Accessed: 03 Mar 2019]
“Cambridge extends world leading role for medical imaging with powerful new brain and body scanners.” Research – News, University of Cambridge, https://www.cam.ac.uk/research/news/cambridge-extends-world-leading-role-for medical-imaging-with-powerful-new-brain-and-body-scanners [Last Accessed: 03 Mar 2019]
Peirce, Andrea. “Hyperpolarized MRI: A New Tool to Assess Treatment Response within Days.” Memorial Sloan Kettering Cancer Centre, Sloan Kettering Institute,
https://www.mskcc.org/blog/hyperpolarized-mri-new-tool-assess-treatment-response within-days [Last Accessed: 03 Mar 2019]
Image Credits:
T-state: Liddington, R. “PDB ID 1HGA.” 1992. Originally published in the Journal of
Molecular Biology 228:551. Reproduced in Lehninger PRINCIPLES of BIOCHEMISTRY
(Seventh Edition). Print.
R-state: Silva, M. “PDB ID 1BBB.” 1992. Originally published in the Journal of
Biological Chemistry 267:17,248. Reproduced in Lehninger PRINCIPLES of BIOCHEMISTRY (Seventh Edition). Print.
Ward, Christopher, et al. “Figure 6. Effect of everolimus treatment on GS-2 tumour
xenografts” Cancer Research, American Association for Cancer Research, Web,
http://cancerres.aacrjournals.org/content/70/4/1296
Curiosity Killed The Cation 