Investigation of the neural basis of expectation-based analgesia in the human brainstem and spinal cord by means of functional magnetic resonance imaging.

PURPOSE: The expected intensity of pain resulting from a noxious stimulus has been observed to have a strong influence on the pain that is perceived. The neural basis of pain reduction, as a result of expecting lower pain, was investigated using functional magnetic resonance imaging (fMRI) in the brainstem and spinal cord. METHODS: Functional MRI studies were carried out in a region spanning the brainstem and cervical spinal cord in healthy participants. Participants were familiarized with a noxious heat stimulus and study procedures in advance, and were informed during each trial that either a heat calibrated to produce moderate pain (Base state), or a temperature 1 °C lower (Low state), would be applied to their hand. However, the Base temperature was applied in every trial. RESULTS: Pain ratings were significantly reduced as a result of expecting lower temperatures. FMRI results demonstrate blood oxygenation-level dependent (BOLD) signal variations in response to participants being informed of the stimulus to expect, in advance of stimulation, and in response to stimulation. Significant coordination of BOLD signals was also detected across specific brainstem and spinal cord regions, with connectivity strengths that varied significantly with the study condition, and with individual pain ratings. The results identify regions that are known to be involved with arousal and autonomic regulation. CONCLUSIONS: Expectation-based analgesia is mediated by descending regulation of spinal cord nociceptive responses. This regulation appears to be related to arousal and autonomic regulation, consistent with the cognitive/affective dimension of pain.

Diversity in the emotional modulation of pain perception: An account of individual variability.

BACKGROUND: While emotional state has been shown to modulate pain perception, there has been little consideration for the individual variability in this effect, or what factors may contribute to individual-level differences. The objective of this study was to characterize the variability in emotional modulation of pain in a healthy sample. METHODS: Twenty-five healthy, adult females participated in a heat pain-rating task. After calibration of the appropriate temperature for each participant, the pain-rating task was combined with viewing of positive, neutral, or negative valence images. Participants rated pain intensity and unpleasantness of the painful stimulus. RESULTS: The magnitude of the effect for emotional modulation of pain was markedly variable across individuals. Some participants exhibited greater pain relief from the positive emotional stimuli while others were more susceptible to pain amplification from the negative emotional stimuli. There were also significant correlations between emotional modulation of pain and specific psychological measures (depression and anxiety). CONCLUSION: Overall, inducing a positive emotional state mitigates pain perception, while negative emotional state amplifies it. The magnitudes of these separate pain-modulating effects, however, vary across individuals, and are associated with individual levels of depressive and anxious feelings, even within a non-clinical population. SIGNIFICANCE: The opposite effects of valence on pain amplification and modulation revealed in this study are novel. This study shows that emotional modulation of pain varies markedly across individuals and is related to psychological factors including depression and anxiety. Examining this link in healthy individuals may inform our understanding of the comorbidity between pain and depression/anxiety.

Diffusion Tensor Imaging of White Matter in Children Born from Preeclamptic Gestations.

BACKGROUND AND PURPOSE: Individuals born from pregnancies complicated by preeclampsia have an elevated risk for cognitive impairment. Deviations in maternal plasma angiokines occur for prolonged intervals before clinical signs of preeclampsia. We hypothesized that fetal brain vascular and nervous tissue development become deviated during maternal progression toward preeclampsia and that such deviations would be detectable by MR imaging. MATERIALS AND METHODS: In this pilot study, 10 matched (gestational and current ages) pairs (5 boys/5 girls, 7-10 years of age) from preeclampsia or control pregnancies were examined by using diffusion tensor MR imaging. An unbiased voxel-based analysis was conducted on fractional anisotropy and mean diffusivity parametric maps. Six brain ROIs were identified for subsequent analysis by tractography (middle occipital gyrus, caudate nucleus and precuneus, cerebellum, superior longitudinal fasciculus, and cingulate gyrus). RESULTS: Statistical differences were present between groups for fractional anisotropy in the caudate nucleus (offspring from preeclamptic gestation > controls), volume of the tract for the superior longitudinal fasciculus (offspring from preeclamptic gestation > controls) and the caudate nucleus (offspring from preeclamptic gestation > controls), and for parallel diffusivity of the cingulate gyrus (offspring from preeclamptic gestation > controls). CONCLUSIONS: These novel preliminary results along with previous results from the same children that identified altered cerebral vessel calibers and increased regional brain volumes justify fully powered MR imaging studies to address the impact of preeclampsia on human fetal brain development.

Brain Structural and Vascular Anatomy Is Altered in Offspring of Pre-Eclamptic Pregnancies: A Pilot Study.

BACKGROUND AND PURPOSE: Pre-eclampsia is a serious clinical gestational disorder occurring in 3%-5% of all human pregnancies and characterized by endothelial dysfunction and vascular complications. Offspring born of pre-eclamptic pregnancies are reported to exhibit deficits in cognitive function, higher incidence of depression, and increased susceptibility to stroke. However, no brain imaging reports exist on these offspring. We aimed to assess brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls. MATERIALS AND METHODS: Offspring of pre-eclamptic pregnancies and matched controls (n = 10 per group) were recruited from an established longitudinal cohort examining the effects of pre-eclampsia. Children underwent MR imaging to identify brain structural and vascular anatomic differences. Maternal plasma samples collected at birth were assayed for angiogenic factors by enzyme-linked immunosorbent assay. RESULTS: Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. Enzyme-linked immunosorbent assay analysis revealed underexpression of the placental growth factor among the maternal plasma samples from women who experienced pre-eclampsia. CONCLUSIONS: This study is the first to report brain structural and vascular anatomic alterations in the population of offspring of pre-eclamptic pregnancies. Brain structural alterations shared similarities with those seen in autism. Vascular alterations may have preceded these structural alterations. This pilot study requires further validation with a larger population to provide stronger estimates of brain structural and vascular outcomes among the offspring of pre-eclamptic pregnancies.

Inter-individual differences in pain processing investigated by functional magnetic resonance imaging of the brainstem and spinal cord.

The experience of pain is a highly complex and personal experience, characterized by tremendous inter-individual variability. The purpose of this study was to use functional magnetic resonance imaging (fMRI) to characterize responses in the brainstem and spinal cord to the same heat stimulus in healthy participants, to further our understanding of individual differences in pain perception. Responses to noxious heat stimuli at 49°C were investigated in 20 healthy individuals by means of fMRI of the brainstem and spinal cord, at 3 Tesla, and were compared with brain fMRI and quantitative sensory testing. Blood oxygenation-level dependent (BOLD) responses were detected with a general linear model (GLM) and effective connectivity was examined with structural equation modeling (SEM). Reported pain ratings ranged from 18 to 84/100 across the participants. Consistent with previous research, brain fMRI results show that BOLD responses in a number of cortical regions are correlated with individual pain ratings. Correlations between pain scores and BOLD responses are also demonstrated in the spinal cord dorsal horn, locus coeruleus, and thalamus. SEM results demonstrate the network of brainstem and spinal cord regions that contribute to the pain response, and reveal differences related to individual pain sensitivity. The results of this study are consistent with the conclusion that individual differences in pain perception in healthy participants are a consequence of differences in descending modulation of spinal nociceptive processes from brainstem regions.

Assessment of data acquisition parameters, and analysis techniques for noise reduction in spinal cord fMRI data.

PURPOSE: The purpose of this work is to characterize the noise in spinal cord functional MRI, assess current methods aimed at reducing noise, and optimize imaging parameters. METHODS: Functional MRI data were acquired at multiple echo times and the contrast-to-noise ratio (CNR) was calculated. Independently, the repetition time was systematically varied with and without parallel imaging, to maximize BOLD sensitivity and minimize type I errors. Noise in the images was characterized by examining the frequency spectrum, and investigating whether autocorrelations exist. The efficacy of several physiological noise reduction methods in both null (no stimuli) and task (thermal pain paradigm) data was also assessed. Finally, our previous normalization methods were extended. RESULTS: The echo time with the highest functional CNR at 3 Tesla is at roughly 75msec. Parallel imaging reduced the variance and the presence of autocorrelations, however the BOLD response in task data was more robust in data acquired without parallel imaging. Model-free based approaches further increased the detection of active voxels in the task data. Finally, inter-subject registration was improved. CONCLUSIONS: Results from this study provide a rigorous characterization of the properties of the noise and assessment of data acquisition and analysis methods for spinal cord and brainstem fMRI.

The current state-of-the-art of spinal cord imaging: methods.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small cross-sectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.

The current state-of-the-art of spinal cord imaging: applications.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small crosssectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.

Advanced MR imaging techniques and characterization of residual anatomy.

Advances in technology in recent decades have contributed to rapid developments in non-invasive methods for imaging human anatomy, and advanced imaging methods are now one of the primary tools for clinical diagnosis after neurological trauma or disease. Here we review the current and upcoming capabilities of one of the most rapidly developing methods, magnetic resonance imaging (MRI). The underlying theory is introduced so that the reasons for the strengths, weaknesses, and future expectations of this method, can be explained. Current techniques for imaging anatomical changes, inflammation, and changes in white matter, axonal integrity, blood flow and function, are reviewed. Applications for specific purposes of assessing traumatic injury in the brain or spinal cord, and for multiple-sclerosis are also presented, and are used as examples of how the advanced techniques are being used in practice.

Tactile sensory and pain networks in the human spinal cord and brain stem mapped by means of functional MR imaging.

BACKGROUND AND PURPOSE: Touch and brush sensory stimuli elicit activity in discriminative touch pathways involving specific regions in the spinal cord and brain stem. However, no study has mapped normal sensory activity noninvasively in healthy humans. The purpose of this study is to map the neuronal activity of sensory input to understand abnormal sensory transmission. MATERIALS AND METHODS: In the present study, spinal fMRI (by using SEEP) was used to map the activity involved with light touch (2 g and 15 g von Frey filaments) and brush stimuli in the brain stem and spinal cords of 8 healthy volunteers. The results were spatially normalized and analyzed with custom-made software. Areas of SEEP activity were identified by using general linear model analysis. RESULTS: The 2 g von Frey filament showed predominant activity in the medulla around the ipsilateral dorsal gracile and cuneate nuclei. The 15 g filament elicited significant activity in the ipsilateral dorsal and contralateral ventral gray matter areas of the spinal cord, areas around the olivary nuclei, pontine reticular formation, periaqueductal gray, and raphe nuclei in the rostral pons and midbrain. The brush stimuli elicited more activity in the medulla around the ipsilateral cuneate and gracile nuclei. CONCLUSIONS: The 2 g filament and brush stimuli activated areas associated with a touch response. The 15 g filament activated areas associated with a pain response. The results from this study identify specific neuronal regions in the brain stem and spinal cord involved in sensory transmission and help understand altered sensory and pain states.

Attenuation of lower-thoracic, lumbar, and sacral spinal cord motion: implications for imaging human spinal cord structure and function.

BACKGROUND AND PURPOSE: Recent literature indicates that cervical and upper-thoracic spinal cord motion adversely affect both structural and functional MR imaging (fMRI; particularly diffusion tensor imaging [DTI] and spinal fMRI), ultimately reducing the reliability of these methods for both research and clinical applications. In the present study, we investigated motion of the lower-thoracic, lumbar, and sacral cord segments to evaluate the incidence of similar motion-related confounds in these regions. MATERIALS AND METHODS: Recently developed methods, used previously for measuring cervical and upper-thoracic spinal cord motion, were employed in the present study to examine anteroposterior (A/P) and left-right (L/R) spinal cord motion in caudal regions. Segmented cinematic imaging was applied with a gradient-echo, turbo fast low-angle shot (turbo-FLASH) pulse sequence to acquire midline images of the cord at 24 cardiac phases throughout the lower-thoracic, lumbar, and sacral spinal cord regions. RESULTS: The magnitude of A/P motion was found to be largest in rostral cord regions, whereas in caudal regions (at the level of the T4/T5 vertebrae and below), peak cord motion was uniformly small (routinely < or =0.10 mm). L/R motion, however, was found to be minimal throughout the thoracic, lumbar, and sacral regions. CONCLUSION: Motion-related errors in spinal fMRI and DTI are expected to be significantly reduced throughout caudal regions of the spinal cord, thus yielding higher sensitivity and specificity compared with rostral regions. The paucity of such errors is expected to provide a means of observing the specific impact of motion (in rostral regions) and to enable the acquisition of uncorrupted DTI and fMRI data for studies of structure and function throughout lumbar and sacral regions.

Spinal fMRI during proprioceptive and tactile tasks in healthy subjects: Activity detected using cross-correlation, general linear model and independent component analysis.

INTRODUCTION: Functional MRI (fMRI) of the spinal cord is able to provide maps of neuronal activity. Spinal fMRI data have been analyzed in previous studies by calculating the cross-correlation (CC) between the stimulus and the time course of every voxel and, more recently, by using the general linear model (GLM). The aim of this study was to compare three different approaches (CC analysis, GLM and independent component analysis (ICA)) for analyzing fMRI scans of the cervical spinal cord. METHODS: We analyzed spinal fMRI data from healthy subjects during a proprioceptive and a tactile stimulation by using two model-based approaches, i.e., CC analysis between the stimulus shape and the time course of every voxel, and the GLM. Moreover, we applied independent component analysis, a model-free approach which decomposes the data in a set of source signals. RESULTS: All methods were able to detect cervical cord areas of activity corresponding to the expected regions of neuronal activations. Model-based approaches (CC and GLM) revealed similar patterns of activity. ICA could identify a component correlated to fMRI stimulation, although with a lower statistical threshold than model-based approaches, and many components, consistent across subjects, which are likely to be secondary to noise present in the data. CONCLUSIONS: Model-based approaches seem to be more robust for estimating task-related activity, whereas ICA seems to be useful for eliminating noise components from the data. Combined use of ICA and GLM might improve the reliability of spinal fMRI results.

Evidence for enhanced functional activity of cervical cord in relapsing multiple sclerosis.

Functional MRI (fMRI) was used to assess proprioceptive-associated cervical cord activity in 24 relapsing multiple sclerosis (MS) patients and 10 controls. Cord and brain conventional and diffusion tensor (DT) MRI were also acquired. fMRI was performed using a block design during a proprioceptive stimulation consisting of a passive flexion-extension of the right upper limb. Cord lesion number, cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA), whole brain and left corticospinal tract lesion volume (LV), gray matter (GM) MD, and normal-appearing white matter (NAWM) MD and FA were calculated. MS patients had higher average cord fMRI signal changes than controls (3.4% vs. 2.7%, P = 0.03). Compared to controls, MS patients also had a higher average signal change in the anterior section of the right cord at C5 (P = 0.005) and left cord at C5-C6 (P = 0.03), whereas no difference was found in the other cord sections. Cord average signal change correlated significantly with cord FA and brain left corticospinal tract LV, GM-MD, and NAWM-FA. This study shows an abnormal pattern of activations in the cervical cord of MS patients following proprioceptive stimulation. Cord fMRI changes might have a role in limiting the clinical consequences of MS associated with irreversible tissue damage.

Magnetic resonance imaging of neuronal and glial swelling as an indicator of function in cerebral tissue slices.

Here we demonstrate a new basis of signal change in magnetic resonance imaging (MRI) related to neuronal function, independent of blood oxygenation or flow. Time series MRI data acquired from living, superfused brain slices of adult rats revealed that the signal intensity reversibly increased with depolarization evoked by briefly elevating extracellular K(+). This was presumably a consequence of increased tissue water in the intracellular compartment. Reversible increases in light transmittance (LT) demonstrating a similar time course in response to K(+) elevation supported cellular swelling as generating the MRI signal intensity changes. This was confirmed by reversibly swelling cells in the slice under hypoosmotic challenge, which increased both MRI and LT signals with an identical time course. Conversely, shrinking cells under hyperosmotic challenge reversibly decreased the MRI and LT signals. We propose that specific MRI of neuronal function (fMRI) signals detected under identical parameters during predominantly proton-density-weighted fMRI of the spinal cord can now be explained by neuronal and glial swelling in activated central nervous system (CNS) regions. These observations demonstrate the biophysical basis of the fMRI contrast mechanism that has been termed "signal enhancement by extravascular water protons," or SEEP.

Investigation of human cervical and upper thoracic spinal cord motion: implications for imaging spinal cord structure and function.

Spinal cord (SC) motion is thought to be the dominant source of error in current diffusion and spinal functional MRI (fMRI) methods. However, until now, such motion has not been well characterized in three dimensions. While previous studies have predominantly examined motion in the superior/inferior (S/I) direction, the foci of the present study were the anterior/posterior (A/P) and right/left (R/L) components of human cervical and upper thoracic SC motion. Cardiac-gated, turbofast low-angle shot (turbo-FLASH) cinematic MRI was employed at 3T to acquire images of the cord at 24 phases throughout the cardiac cycle. Time-dependent signal fluctuations within voxels adjacent to the cord/cerebrospinal fluid (CSF) interface were then used to measure SC motion, which was found to occur predictably as a function of cardiac activity. Cord movement was largest in the A/P direction, for which principal components of motion were calculated, thereby indicating consistent patterns of SC oscillation that can potentially be used to improve SC imaging.

Detection of the neuronal activity occurring caudal to the site of spinal cord injury that is elicited during lower limb movement tasks.

STUDY DESIGN: Functional magnetic resonance imaging (fMRI) of the spinal cord (spinal fMRI) was used to detect neuronal activity elicited by passive and active lower limb movement tasks, in regions caudal to the injury site in volunteers with spinal cord injury. OBJECTIVES: The objectives of this project are: (1) to assess the use of spinal fMRI as a tool for detecting neuronal function in the spinal cord below an injury, and (2) to characterize the neuronal response to active and passive movement tasks. SETTING: Institute for Biodiagnostics, National Research Council of Canada, Winnipeg, Manitoba, Canada. METHODS: fMRI of the spinal cord was carried out in 12 volunteers with cervical or thoracic spinal cord injuries. Spinal fMRI was carried out in a 1.5 T clinical MR system using established methods. Active and passive lower limb movement tasks were performed, and sagittal images spanning the entire lumbar spinal cord were obtained. RESULTS: Activity was detected in all volunteers regardless of the extent of injury. During both active and passive participation, activity was seen caudal to the injury site, although the number of active voxels detected with passive movement was less than with the active movement task. Average percent signal change was 13.6% during active participation and 15.0% during passive participation. CONCLUSIONS: Spinal fMRI is able to detect a neuronal response during both active and passive lower limb movement tasks in the spinal cord caudal to the injury site.

Discrimination of errors from neuronal activity in functional MRI of the human spinal cord by means of general linear model analysis.

Functional MRI (fMRI) of the spinal cord has been demonstrated to provide reliable and sensitive maps of neuronal activity, particularly when combined across several experiments. Individual experiments reveal neuronal activity as well as errors. The dominant source of errors is hypothesized to be physiological motion, including cardiac and respiratory motion, flow of blood and cerebrospinal fluid (CSF), and motion of the spinal cord within the spinal canal. All of the hypothesized sources of error are therefore related to cardiac and respiratory motion, which can be recorded during an fMRI experiment. Analyses were carried out with a general linear model (GLM) with peripheral pulse and respiration recordings used as models of errors. The results demonstrate that the sensitivity of spinal fMRI is improved and errors are reduced when peripheral pulse traces are used in the GLM, but no improvement was detected with the inclusion of respiratory traces.

Simultaneous functional magnetic resonance imaging in the rat spinal cord and brain.

Functional magnetic resonance imaging (fMRI) method was developed to investigate the pattern and temporal relationship in neuronal pathways of brain and spinal cord. Signal intensity changes correlating with stimulation patterns were observed simultaneously in the rat spinal cord and brain using fMRI at 9.4 T. Electrical stimulation of the forepaw was used to elicit activity. A quadrature volume RF coil covering both brain and the cervical spinal cord was used. Sets of fast spin echo (FSE) images were acquire simultaneously for both brain and spinal cord fMRI. Experiments were repeated in single animal and across animals. Activities within the dorsal horn of the spinal cord and within the somatosensory cortex were observed consistently within each animal as well as across animals.

fMRI of the lumbar spinal cord during a lower limb motor task.

This study applied spinal fMRI to the lumbar spinal cord during lower limb motor activity. During active ankle movement, activity was detected in the lumbar spinal cord motor areas and sensory areas bilaterally. During passive ankle movement, activity was detected in the motor and sensory areas in lower lumbar spinal cord segments and motor activity in higher lumbar spinal cord segments. Spinal fMRI detects patterns of activity consistent with known physiology and can be used to reliably assess activity in the lumbar spinal cord during lower limb motor stimulation. This study affirms spinal fMRI as an effective tool for assessing spinal cord function and increases its potential as a clinical tool.

Noninvasive assessment of the injured human spinal cord by means of functional magnetic resonance imaging.

STUDY DESIGN: A magnetic resonance imaging technique that enables indirect detection of neuronal activity has been developed for the spinal cord. In the present study, this method, spinal functional magnetic resonance imaging (fMRI), is applied to the first study of the injured spinal cord, with the goal of better clinical assessment of the entire cord. OBJECTIVES: The objectives of this project are: (1) to investigate the neuronal activity that can be detected in the spinal cord caudal to a chronic injury by means of spinal fMRI, and (2) to develop spinal fMRI as a clinical diagnostic tool. SETTING: Institute for Biodiagnostics, National Research Council of Canada, Winnipeg, Manitoba, Canada. METHODS: fMRI of the spinal cord was carried out in 27 volunteers with cervical or thoracic spinal cord injuries (SCIs). Of these volunteers, 18 had complete injuries, and nine had incomplete injuries. Spinal fMRI was carried out in a 1.5 T clinical MR system, using established methods. Thermal stimulation at 10 degrees C was applied to the fourth lumbar dermatome on each leg, and images were obtained of the entire lumbar spinal cord. RESULTS: Areas of neuronal activity were consistently observed in the lumbar spinal cord in response to the thermal stimulation, even when the subjects had no awareness of the sensation. The pattern of activity was notably different compared with noninjured subjects. In general, subjects with complete SCI showed absent or diminished dorsal gray matter activity, but had enhanced ventral activity, particularly contralateral to the stimulation. CONCLUSIONS: Spinal fMRI is able to provide a noninvasive assessment of the injured spinal cord that does not depend on the patient's perception of the stimulus being applied. This work was carried out on a standard clinical MRI system without modification, and so is readily applicable in most MR units. SPONSORSHIP: This work was funded by a grant from the Canadian Institutes of Health Research (CIHR).