Alexander MacKay


Relevant Degree Programs


Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
T₁ relaxation and inhomogeneous magnetization transfer in brain : physics and applications (2019)

A major goal of the Magnetic Resonance Imaging (MRI) community is quantifying myelin in white matter. MRI contrast depends on tissue microstructure, so quantitative models require detailed understanding of Nuclear Magnetic Resonance (NMR) physics in white matter's complex, heterogeneous environment. In this thesis, we study the underlying physics behind two different ¹H contrast mechanisms in white and grey matter tissue: T₁ relaxation and the recently developed inhomogeneous Magnetization Transfer (ihMT).Using ex-vivo white and grey matter samples of bovine brain, we performed a comprehensive solid-state NMR study of T₁ relaxation under six diverse initial conditions. For the first time, we used lineshape fitting to quantify the non-aqueous magnetization during relaxation. A four pool model describes our data well, matching with earlier studies. We also show examples of how the observed T₁ relaxation behaviour depends upon the initial conditions.ihMT's sensitivity to lipid bilayers, like those in myelin, was originally thought to rely upon hole-burning in the supposedly inhomogeneously-broadened lipid lineshape. Our work shows that this is incorrect and that ihMT only requires the presence of dipolar couplings, not a specific kind of line broadening. We developed a simple explanation of ihMT using a spin-1 system. Using solid-state NMR, we then performed measurements of ihMT and T₁D (dipolar order relaxation time) on four samples: a multilamellar lipid system (Prolipid-161), wood, hair, and bovine tendon. ihMT was observed in all samples, even those with homogeneous broadening (wood and hair). Moreover, we saw no evidence of hole-burning.Lastly, we present results from ihMT experiments with CPMG acquisition on the bovine brain samples. We show that myelin water has a higher ihMT signal than water outside the myelin. It was determined that this was due to the unique thermal motion in myelin lipids. In doing so, we developed a useful metric for determining the relative contributions from magnetization transfer and dipolar coupling to ihMT. Also, we applied a qualitative four pool model with dipolar reservoirs. Together, our results are consistent with myelin lipids having a T₁D which is appreciably longer than the T₁D of non-myelin lipids, despite recent measurements to the contrary.

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Localized bladder dose accumulation in multi-fraction cervical cancer brachytherapy (2017)

Radiation therapy in the definitive treatment of locally advanced carcinoma of the cervix consists of external beam radiotherapy (EBRT) combined with image-guided high-dose-rate (IG HDR) intracavitary brachytherapy (ICBT). IG HDR-ICBT is a relatively new, advanced form of brachytherapy treatment planning and delivery that still relies largely on dose criteria based either on clinical experience using older techniques, or on limited data. Calculation of cumulative dose received over multiple treatment fractions currently utilizes dose-volume-histograms (DVH), which do not provide information about the spatial distribution of dose within the structures ofinterest. Since most of the organs at risk (OAR) for this site, like the bladder and rectum, are highly deformable, DVH data summed over multiple treatment fractions do not provide accurate estimates of the cumulative dose to specific regions of the organ, and therefore may not be the most appropriate metric to use in treatment planning and dose assessment. The primary goal of this thesis was, therefore, to develop methods to more accurately quantify “locally accumulated” dose to the bladder-wall in multi-fraction IG HDR-ICBT for cervical cancer using deformable registration, and to apply these to a study of locally-accumulated dosimetric parameters as predictors of late urinary toxicity. To this end, different deformable image and point-set registration methods were evaluated, using phantom data, for their ability to register bladder-wall contours of various sizes. The best of these was retrospectively applied to point-setsrepresenting the bladder-wall in multiple HDR treatment fractions for 60 cervical cancer patients treated at the BC Cancer Agency. The transformation maps obtained from the registrations were used to calculate cumulative dose parameters for the bladder-wall and the urethral opening to the bladder (bladder neck). Patients were divided into Case and Control groups based on urinary toxicity scores for different symptoms, and the ability of the cumulative parameters to predict toxicity was evaluated. It was concluded that some locally-cumulative parameters estimated using our method have improved potential for predicting urinary toxicity, as compared to traditional DVH-based parameters, in our data set. In addition, dose to small volumes around the bladder neck was found to be a predictor of incontinence.

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Accurate measurement of brain water content by magnetic resonance (2015)

Accurate measurement of total water content (TWC) is valuable for assessing changes in brain water such as edema, which occurs with many neurological diseases, as well as monitoring the effects of treatments. T2 relaxation has been used to measure TWC in brain on 1.5T magnetic resonance imaging (MRI) scanners. This method was modified for 3T in order to ensure accuracy in the presence of increased radiofrequency field inhomogeneities. Phantom validations demonstrated excellent agreement between MRI-measured TWC and known water concentrations of tubes. Simulations indicated a 3% mean error in TWC estimation. Homogeneous TWC maps were produced in the brain of 10 healthy human subjects; TWC values agreed with literature. Two different receiver coil inhomogeneity corrections were compared in the same 10 subjects, as well as 2 multiple sclerosis (MS) patients – one which requires the measurement of a low flip angle image, and the other based on comparison to a homogeneous pseudo TWC map calculated from T1. Both techniques resulted in similar, homogeneous TWC maps in healthy brain, although differences up to 2% were measured in abnormal MS brain tissue.Finally, the TWC method was implemented for two applications. 20 subjects were scanned after consuming 3L of water and again after 9 hours of fasting to determine whether hydration affects brain TWC and volume. No significant changes were measured, indicating that homeostasis mechanisms likely regulated brain TWC during the short term fluid shifts. Some MS drugs have been shown to cause initial accelerated brain volume loss, which is hypothesized to be due to water loss. In the second application, TWC of normal appearing tissue and whole brain and brain volume were measured in 16 MS patients over a 6 month course of treatment with interferon beta. A trend of decreasing brain volume between months 3 and 6 was concurrent with a reduction in whole brain TWC, suggesting that accelerated brain volume loss on interferon beta may be due to reduced inflammation or edema in abnormal appearing tissue. Here we present a useful tool that can be used at 3T to simultaneously assess changes in water and myelin in neurological diseases.

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Characterizing magnetization exchange in healthy human brain and bovine brain (2014)

Multi component T₂ relaxation imaging is an established MRI technique for measuring myelin water (MW, water molecules trapped between myelin sheath bilayers). Myelin water fraction (MWF, the fraction of central nervous system water with a short T₂) has been quantitatively correlated to histological staining for myelin in central nervous system tissue and hence is considered an in vivo measure of myelin content. Various studies have reported on the measurement of MWF with a diverse range of neurological diseases such as Multiple Sclerosis (MS), Schizophrenia, epilepsy, and Phenylketonuria (PKU).Although T₂ relaxation is the main probe for measuring MWF, understanding longitudinal relaxation, T1, is essential in a number ways such as the following: 1) Estimation of the corrections for myelin water fraction that need to be taken into account due to water exchange processes in white matter in vivo is highly dependent on T₁ relaxation. 2) Investigating the effect of T1-weighting in MWF measurements at short TR. This is especially important due to recent breakthroughs in developing rapid 3-D whole brain approaches to MWF measurements that are pushing towards shorter and shorter TR times in order to make this technique a valuable clinical imaging tool. First, in vivo MRI data from multi-component T₂ relaxation from 57 healthy subjects collected at 3.0 T was analyzed to estimate the corrections which have to be taken into account due to magnetization exchange in white matter. These results showed that these MWF corrections were less than 15% and are uniform across various white matter structures.Next, the variation of MWF as function of repetition time (TR) was investigated using in vivo MRI data collected at 3.0 T from healthy subjects. These results clearly showed that the measured MWF increased as the TR decreased.Finally, in order to measure T₁ as well as the rate of magnetization exchange with higher precision, data from bovine brain white matter was collected using a 4.7 T NMR spectrometer. The results from this study clearly showed that the T₁ had two components; therefore magnetization in bovine white matter is not in a fast exchange regime on the T₁ timescale.

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Myelin water imaging : development at 3.0T, application to the study of multiple sclerosis, and comparison to diffusion tensor imaging (2009)

T2 relaxation imaging can be used to measure signal from water trapped between myelin bilayers; the ratio of myelin water signal to total water is termed the myelin water fraction (MWF). First, results from multi-component T2 relaxation and diffusion tensor imaging (DTI) were compared for 19 multiple sclerosis (MS) subjects at 1.5 T to better understand how each measure is affected by pathology. In particular, it was determined that the detection of a long-T2 signal within an MS lesion may be indicative of a different underlying pathology than is present in lesions without long-T2 signal. Next, the single-slice T2 relaxation measurement was implemented, refined, and validated at 3.0 T. Scan parameters were varied for phantoms and in-vivo brain, and changes in multi-exponential fit residuals and T2 distribution-derived parameters such as MWF were monitored to determine which scan parameters minimized artifacts. Measurements were compared between 1.5 T and 3.0 T for 10 healthy volunteers. MWF maps were qualitatively similar between field strengths. MWFs were significantly higher at 3.0 T than at 1.5 T, but with a strong correlation between measurements at the different field strengths. Due to long acquisition times, multi-component T2 relaxation has thus far been clinically infeasible. The next study aimed to validate a new 3D multi-component T2 relaxation imaging technique against the 2D single-slice technique most commonly used. Ten healthy volunteers were scanned with both the 2D single-slice and 3D techniques. MWF maps were qualitatively similar between scans. MWF values were highly correlated between the acquisition methods. Although MWF values were generally lower using the 3D technique, they were only significantly so for peripheral brain structures, likely due to increased sensitivity of slab-selective refocusing pulses used for the 3D approach. The 3D T2 relaxation sequence was then applied to the study of MS to take advantage of the increased brain coverage. Thirteen MS subjects and 11 controls underwent T2 relaxation and DTI examinations to produce histograms of MWF and several DTI-derived metrics. MS MWF histograms differed considerably from those of controls, and differences in MS MWF histograms did not mirror differences in DTI histograms relative to matched controls.

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Master's Student Supervision (2010 - 2018)
Characterization of myelin water imaging using a gradient and spin echo sequence in human brain and spinal cord (2016)

Myelin water imaging is a quantitative magnetic resonance imaging technique that can be used as an in vivo biomarker for myelin in the central nervous system. In 2007, a paradigm shift took place when the standard sequence for myelin water imaging changed from a multi-echo spin echo sequence to a gradient and spin echo (GRASE) sequence. The GRASE sequence has so far only been applied to brain imaging, and reproducibility between different scan vendors has not been assessed. In this study I present the first implementation of myelin water imaging using GRASE in human cervical spinal cord. The reproducibility of myelin water imaging in the spinal cord was found to be high (coefficient of variation = 6.1%, Cronbach’s α = 0.89). A multicenter reproducibility study of myelin water imaging in brain between two scan vendors (Siemens and Philips) was also performed. Results from the two scanners were found to be highly correlated but with a significant offset in myelin water fraction of 4.3%. Together, these two studies provide strong evidence of the reproducibility of myelin water imaging. It is an important step forward in the development of bringing myelin water imaging to the mainstream.

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Investigating the myelin water fraction as a function of TR and the intra/extra cellular water geometric mean T2 as a function of refocusing interval (2014)

In this thesis two studies were done using MRI. In chapter two, in vivo 3.0 T MRI data from white matter and grey matter in brain from 4 healthy volunteers was studied using a multi component T₂ relaxation analysis. The goal of this study was to find the dependence of myelin water fraction (MWF), the ratio of water in myelin bilayers to the total water component, with the repetition time of the MR sequence TR. Results showed that MWF increased with decreasing TR time. This behavior is believed to be influenced by the exchange of water between the myelin water and the intra/extracellular water pools. Several models were explored to explain this result, including a fast exchange model, a slow exchange model and a hybrid model in which myelin was proposed to contain regions of fast exchange and regions of slow exchange.In chapter three, we addressed the questions: Does the intra/extra cellular (IE) water geometric mean T₂ (gmT₂) of white and grey matter depend upon the refocusing interval? To answer these questions IE water gmT₂ times for different white and grey matter regions of interest were obtained from 5 healthy subjects. It was found that IE water gmT₂ times from both white matter and grey matter tissue decreased by approximately the same amount with refocusing interval prolongation from 10ms to 40 ms. Several mechanisms for this dependence were considered, including water exchange, existence of myelin, non-heme iron accumulation, or the effect of blood oxygenation. In this case, based on our simulations, exchange did not appear to play a role. Non-heme iron accumulation was related to T₂ time but not to the change in T₂ with echo spacing. Deoxygenation of blood results in the presence of paramagnetic deoxyhemoglobin (dHb), which increases the magnetic susceptibility, and thus the local magnetic field, which can shorten the transverse relaxation time; however, this mechanism would be expected to affect grey matter T₂’s more than white matter T₂s.

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Using an ultrasound-derived model to assist in dosimetry for prostate cancer treatment through brachytherapy (2013)

Prostate cancer is the most common form of cancer affecting men in Canada. Patients with localized, early stage disease are often treated using prostate brachytherapy, a technique that involves surgically implanting small radioactive capsules or “seeds” in the prostate. Implantation is performed under the guidance of transrectal ultrasound (TRUS) imaging, and treatment is assessed postoperatively for quality assurance purposes. Pelvic CT imaging is used to evaluate the dose delivered to the target; however, it is a challenge to consistently and confidently identify prostate boundaries due to thepoor soft tissue contrast on CT. This leads to large variability in CT-defined anatomical contours and calculated dosimetric quality assurance parameters, and has led to increased reliance on other imaging technologies such as MR. Meanwhile, TRUS typically provides high-quality anatomical visualization, but provides insufficient information for dose calculation purposes. We have developed a new method to transfer ultrasound-based contours to CT images using mathematical modeling and a novel registration technique. The prostate model, derived from TRUS contours, is generated via two streams: one assumes a modified ellipsoid shape (model X), and the other performs a straightforward linear interpolation (model Y). Both are manipulated to account for expected deformations such as TRUS-probe compression and edema. Registration from TRUS to CT spatial coordinatesis based on matched seed locations. We evaluate the quality of model-generated contours primarily by comparing the measured volume and dosimetric parameters to the observed variability range determined from manual CT contours. In 19 of model X, and 18 of model Y, cases out of 20, volumes produced were within the variability observed from 5 experienced physicians. However, dose parameters agreed in only a moderate number of cases (9–13), partly motivating a region-specific analysis. We found the least agreement in the posterior apex, with model contours tending to be larger. We discuss the possible reasons for this, as well as implications on the role of modeling in an applied clinical setting. Ultimately, the ultrasound-informed model shows promise, and has many benefits relative to other methods, such thosebased on CT or MR.

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Characterizing T₂ distributions in healthy white matter (2011)

Quantitative T₂ measurements in Magnetic resonance imaging (MRI) can provide information about water environments in biological structures. Here, an extended Carr-Purcell-Meiboom-Gill sequence (CPMG) with echoes out to 1120ms was used to characterize Long-T₂ times of healthy white matter in brain. One of the white matter structures, the corticospinal tract (CST), was previously found to be bright on T₂-weighted images and myelin water fraction (MWF) images. The intra-/extra- cellular water (IE) T₂ peak of the CST was found to be broadened in comparison to that from other white matter structures and often split into two distinct peaks. In the CST, it appeared that the intracellular and extracellular water environments had different T₂ times, causing the intracellular water peak to be pushed down into the myelin water T₂ regime and the extracellular peak to be pushed up to higher T₂ times. The conventional T₂ limits of 10−40ms used for the MWF at 1.5T result in an artificial increase in MWF, which causes the CST to be bright on myelin water images. When the upper limit of the MWF range was decreased to 25ms, the CST exhibited MWF values similar to those found for adjacent anterior and posterior regions.Using T₂ time of 25ms for the myelin water (MW) upper limit and IE lower limit, a moderately strong relationship between IE geometric mean T₂ (GMT₂) and MW was found across all structures and subjects. This relationship did not necessarily hold when examined across subjects within individual structures The relationship between IE GMT₂ and MWF could arise from a non-biological source, such as the algorithm used in calculating T₂ or from a biological source, such as exchange between the water environments or increased extracellular water. Based on our results the fitting algorithm does not appear to be responsible for this relationship based on our results. However, either varying amounts of extracellular water or exchange between MW and IE could explain this relationship.

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Quantifying development : using T₂ relaxation to investigate myelination of the corpus callosum in preadolescents (2010)

This thesis describes a novel voxel‐based analysis of the transverse (T₂) relaxation decay curve to quantify myelin water fraction (MWF). Multi‐echo T₂ relaxation decay data was acquired for 5 preadolescent males (age range 9 – 12 years). A novel signal to noise filter appropriate for multi‐exponential T₂ analysis was then applied to remove voxels which did not accurately fit the modelled curve. The remaining voxels were designated “highly myelinated” if their MWF was greater than a certain critical value. A range of signal to noise filter cut‐off values and highly myelinated critical values were investigated. This thesis demonstrates, for the first time, a very strong and significant correlation (r = 0.990, p = 0.001) between verbal intelligence quotient scores on the Wechsler Intelligence Scale for Children – Revised and myelination in the corpus callosum of developing children. This relationship is supported by a growing number of studies showing a correlation between white matter development and cognitive ability. In addition, due to the restricted age range of our subjects, this work is able to show the individual variations in myelin maturation rates.

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