Why Use MRI in Biomedical Research?
Magnetic Resonance Imaging (MRI) has become a useful diagnostic tool since its introduction into the clinic over 30 years ago. Researchers have equally recognized its value in monitoring a variety of biological systems, from simple protein solutions to animals and humans. Along with its obvious use as a clinical research tool, MRI has gained popularity in studying preclinical animal models of human disease and disorder. MRI is characterized by two advantages that are attractive in preclinical research: the ability to monitor in vivo biological variables noninvasively, and the ability to serially track the progression of a disease or intervention in the same living animal, thus improving a study’s biological and translational relevance. MRI can measure a wide array of biological variables, ranging from morphological information to parameters relating to tissue function. More recently, MRI has made forays into “molecular imaging” where cellular and biochemical events are indirectly detected through the use of targeted contrast agents. The implementation of these increasingly complex MRI techniques is not straightforward, and requires intimate knowledge of the physics and mechanisms behind the measurements.
The following sections provide some examples of previous and ongoing projects at the UBC MRI Research Centre as well as promising new applications that could potentially be implemented at the Centre.
Morphological Imaging: High Resolution at Arbitrary Orientations
Morphological imaging is important for distinguishing differences in anatomy due to disease progression or phenotype. MRI performs very well in measuring anatomical detail due to excellent image contrast between individual soft tissue types (e.g. water vs. fat, normal vs. cancerous). Acquiring good images at high resolution is challenging with in vivo specimens, with a voxel size of 0.1×0.1×0.5 mm being achievable through careful experimental design and moderately long acquisition times.
MRI will never be able to match the exquisite resolution available in optical histology methods, but does offer the opportunity to nondestructively acquire volumetric images of a living animal in virtually any orientation. Image quality and resolution further improves with ex vivo specimens, with other investigators reporting isotropic resolutions as small as 50 microns (fixed mouse specimens with overnight scanning times). In addition, MRI can measure the overall effect of structures much smaller than the voxel size; a classic example is “diffusion imaging”, which measures the amplitude of the microscopic diffusion processes which influence the MRI signal.
Functional Imaging: Investigating Biological Processes
Apart from morphological imaging, current MRI applications have tended towards measuring the function of biological systems, which further clarifies the “mechanism of action” which underlie a disease process or therapeutic intervention. For example, magnetic resonance spectroscopy (MRS) can be used to study metabolic processes through measurement of in vivo metabolite concentrations: it is possible to detect high-energy phosphates and hydrogen-based metabolites in brain, heart, muscle and tumour.
Vascular parameters such as blood flow and vessel permeability can also be investigated, most commonly through rapid monitoring of signal enhancement while an intravenously injected contrast agent passes through the organ of interest. Finally, one technique that has gained great popularity is the so-called “functional MRI” (fMRI) technique, where MRI signal changes in the nervous system reflect increases in local blood flow, which are interpreted as the effect of local neurological activity. fMRI has gained wide acceptance in the human neuroscience and psychology fields; however its application to animal models is still a matter of ongoing development.
Molecular Imaging: Detection of Cellular Events and Beyond
The current frontier in preclinical MRI research is “molecular imaging”, which aims to noninvasively detect events on the cellular and subcellular level. This approach typically involves attaching a payload of MRI-visible contrast agent to a cell or nanoparticle that would otherwise be undetectable under MRI. In this way, therapeutic agents such as drugs, lentiviral vectors, and stem cells can be “labeled” in order to monitor the biodistribution and pharmacokinetics of the agent following injection. Another approach is to conjugate the MRI contrast agent with a ligand which preferentially binds to specific endogenous receptors, opening up the possibility to detect the expression of enzymes or receptors that arise in specific biochemical pathways. By far, the biggest challenge with using MRI for molecular imaging is its low sensitivity; MRI contrast agent concentrations must at least be in the micromolar range, whereas radiotracer contrast agents used in positron emission tomography (PET) can be detected in the picomolar range. However, MRI does provide the advantage of acquiring images that elucidate both the “molecular” events as well as the anatomy in the same experiment with the same instrument.
Here we list some of the peer-reviewed publications generated from the facility within recent years:
Moosvi F, Baker JHE, Yung A, Kozlowski P, Minchinton AI, Reinsberg SA. Fast and sensitive dynamic oxygen-enhanced MRI with a cycling gas challenge and independent component analysis. Magn Reson Med. 2019 Apr;81(4):2514-2525. doi: 10.1002/mrm.27584. Epub 2018 Oct 28. PMID: 30368892.
Baker JHE, Kyle AH, Reinsberg SA, Moosvi F, Patrick HM, Cran J, Saatchi K, Häfeli U, Minchinton AI. Heterogeneous distribution of trastuzumab in HER2-positive xenografts and metastases: role of the tumor microenvironment. Clin Exp Metastasis. 2018 Oct;35(7):691-705. doi: 10.1007/s10585-018-9929-3. Epub 2018 Sep 8. PMID: 30196384; PMCID: PMC6209006.
Baker JH, McPhee KC, Moosvi F, Saatchi K, Häfeli UO, Minchinton AI, Reinsberg SA. Multi-modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG-GdF). Contrast Media Mol Imaging. 2016 Jan-Feb;11(1):77-88. doi: 10.1002/cmmi.1661. Epub 2015 Aug 13. PMID: 26268906.
Yapp DT, Wong MQ, Kyle AH, Valdez SM, Tso J, Yung A, Kozlowski P, Owen DA, Buczkowski AK, Chung SW, Scudamore CH, Minchinton AI, Ng SS. The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth. Angiogenesis. 2016 Apr;19(2):229-44. doi: 10.1007/s10456-016-9503-z. Epub 2016 Mar 9. PMID: 26961182; PMCID: PMC4819514.
Moroz J, Wong CL, Yung AC, Kozlowski P, Reinsberg SA. Rapid measurement of arterial input function in mouse tail from projection phases. Magn Reson Med. 2014 Jan;71(1):238-45. doi: 10.1002/mrm.24660. Epub 2013 Feb 14. PMID: 23413008.
Cham KK, Baker JH, Takhar KS, Flexman JA, Wong MQ, Owen DA, Yung A, Kozlowski P, Reinsberg SA, Chu EM, Chang CW, Buczkowski AK, Chung SW, Scudamore CH, Minchinton AI, Yapp DT, Ng SS. Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60. doi: 10.1038/sj.bjc.6605727. Epub 2010 Jun 8. PMID: 20531411; PMCID: PMC2905290.
Desrochers J, Yung A, Stockton D, Wilson D. Depth-dependent changes in cartilage T2 under compressive strain: a 7T MRI study on human knee cartilage. Osteoarthritis Cartilage. 2020 Sep;28(9):1276-1285. doi: 10.1016/j.joca.2020.05.012. Epub 2020 May 29. PMID: 32474193.
Greaves LL, Gilbart MK, Yung AC, Kozlowski P, Wilson DR. Effect of acetabular labral tears, repair and resection on hip cartilage strain: A 7T MR study. J Biomech. 2010 Mar 22;43(5):858-63. doi: 10.1016/j.jbiomech.2009.11.016. Epub 2009 Dec 16. PMID: 20015494.
Greaves LL, Gilbart MK, Yung A, Kozlowski P, Wilson DR. Deformation and recovery of cartilage in the intact hip under physiological loads using 7T MRI. J Biomech. 2009 Feb 9;42(3):349-54. doi: 10.1016/j.jbiomech.2008.11.025. Epub 2009 Jan 14. PMID: 19147144.
Loonen ICM, Jansen NA, Cain SM, Schenke M, Voskuyl RA, Yung AC, Bohnet B, Kozlowski P, Thijs RD, Ferrari MD, Snutch TP, van den Maagdenberg AMJM, Tolner EA. Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice. Brain. 2019 Feb 1;142(2):412-425. doi: 10.1093/brain/awy325. PMID: 30649209; PMCID: PMC6351775.
Cain SM, Bohnet B, LeDue J, Yung AC, Garcia E, Tyson JR, Alles SR, Han H, van den Maagdenberg AM, Kozlowski P, MacVicar BA, Snutch TP. In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2401-2406. doi: 10.1073/pnas.1614447114. Epub 2017 Feb 21. PMID: 28223480; PMCID: PMC5338525.
Spinal Cord Injury
Phillips AA, Matin N, Jia M, Squair JW, Monga A, Zheng MMZ, Sachdeva R, Yung A, Hocaloski S, Elliott S, Kozlowski P, Dorrance AM, Laher I, Ainslie PN, Krassioukov AV. Transient Hypertension after Spinal Cord Injury Leads to Cerebrovascular Endothelial Dysfunction and Fibrosis. J Neurotrauma. 2018 Feb 1;35(3):573-581. doi: 10.1089/neu.2017.5188. Epub 2018 Jan 2. PMID: 29141501; PMCID: PMC6421994.
Yung A, Mattucci S, Bohnet B, Liu J, Fournier C, Tetzlaff W, Kozlowski P, Oxland T. Diffusion tensor imaging shows mechanism-specific differences in injury pattern and progression in rat models of acute spinal cord injury. Neuroimage. 2019 Feb 1;186:43-55. doi: 10.1016/j.neuroimage.2018.10.067. Epub 2018 Oct 26. PMID: 30409758.
Bhatnagar T, Liu J, Yung A, Cripton P, Kozlowski P, Tetzlaff W, Oxland T. Relating Histopathology and Mechanical Strain in Experimental Contusion Spinal Cord Injury in a Rat Model. J Neurotrauma. 2016 Sep 15;33(18):1685-95. doi: 10.1089/neu.2015.4200. Epub 2016 Apr 8. PMID: 26729511; PMCID: PMC5035832.
Bhatnagar T, Liu J, Yung A, Cripton P, Kozlowski P, Tetzlaff W, Oxland T. Quantifying the internal deformation of the rodent spinal cord during acute spinal cord injury – the validation of a method. Comput Methods Biomech Biomed Engin. 2016;19(4):386-95. doi: 10.1080/10255842.2015.1032944. Epub 2015 Apr 20. PMID: 25894327.
Bhatnagar T, Liu J, Yung A, Cripton PA, Kozlowski P, Oxland T.. Ann Biomed Eng. 2016 Apr;44(4):1285-98. doi: 10.1007/s10439-015-1412-6. Epub 2015 Aug In Vivo Measurement of Cervical Spinal Cord Deformation During Traumatic Spinal Cord Injury in a Rodent Model 21. PMID: 26294007.
Laing AC, Brenneman EC, Yung A, Liu J, Kozlowski P, Oxland T. The effects of age on the morphometry of the cervical spinal cord and spinal column in adult rats: an MRI-based study. Anat Rec (Hoboken). 2014 Oct;297(10):1885-95. doi: 10.1002/ar.22995. Epub 2014 Jul 18. PMID: 25044631.
Kozlowski P, Rosicka P, Liu J, Yung AC, Tetzlaff W. In vivo longitudinal Myelin Water Imaging in rat spinal cord following dorsal column transection injury. Magn Reson Imaging. 2014 Apr;32(3):250-8. doi: 10.1016/j.mri.2013.12.006. Epub 2013 Dec 27. PMID: 24462106; PMCID: PMC5462368.
Kozlowski P, Raj D, Liu J, Lam C, Yung AC, Tetzlaff W. Characterizing white matter damage in rat spinal cord with quantitative MRI and histology. J Neurotrauma. 2008 Jun;25(6):653-76. doi: 10.1089/neu.2007.0462. PMID: 18578635.
Laule C, Yung A, Pavolva V, Bohnet B, Kozlowski P, Hashimoto SA, Yip S, Li DK, Moore GW. High-resolution myelin water imaging in post-mortem multiple sclerosis spinal cord: A case report. Mult Scler. 2016 Oct;22(11):1485-1489. doi: 10.1177/1352458515624559. Epub 2016 Jan 27. PMID: 26819263.
Contrast Agent Development
Topping GJ, Yung A, Schaffer P, Hoehr C, Kornelsen R, Kozlowski P, Sossi V. Manganese concentration mapping in the rat brain with MRI, PET, and autoradiography. Med Phys. 2017 Aug;44(8):4056-4067. doi: 10.1002/mp.12300. Epub 2017 Jul 5. PMID: 28444763.
Misri R, Meier D, Yung AC, Kozlowski P, Häfeli UO. Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobe. Nanomedicine. 2012 Aug;8(6):1007-16. doi: 10.1016/j.nano.2011.10.013. Epub 2011 Nov 16. PMID: 22100757.
Sahebjavaher RS, Nir G, Gagnon LO, Ischia J, Jones EC, Chang SD, Yung A, Honarvar M, Fazli L, Goldenberg SL, Rohling R, Sinkus R, Kozlowski P, Salcudean SE. MR elastography and diffusion-weighted imaging of ex vivo prostate cancer: quantitative comparison to histopathology. NMR Biomed. 2015 Jan;28(1):89-100. doi: 10.1002/nbm.3203. Epub 2014 Nov 10. PMID: 25382459; PMCID: PMC5478374.
UBC MRI Research Centre: Helping Researchers Find Answers
The UBC MRI Research Centre was established to support the local biomedical research community with the resources and expertise necessary to implement MRI techniques in their research. The main centrepiece of our preclinical research capabilities is a 7 Tesla MRI scanner designed specifically for small experimental animals such as mice and rats. We take pride in providing a full range of research support for MR imaging and spectroscopy applications including method development, data collection and data analysis. Our approach is very much a collaborative one, with user research driving new technique development and vice versa. The costs associated with system maintenance, scanner operation and method development are recovered through an hourly rate applied during the imaging sessions. Highlights of our facility infrastructure include:
- Bruker Biospec 7 Tesla MRI scanner (4 receiver channels, 20 cm-diameter accessible bore size)
- In-scan isofluorane anesthesia system and body temperature control
- Monitoring system for vital signs (temperature, respiration and ECG)
- Animal prep room for scan preparation and small surgeries
- Electronics/machining workshop and computing facilities
- Three full-time staff including a physicist, engineer and scanner operator
If you are interested in using our facility, please contact us to arrange an initial consultation.