QUANTITATIVE ASSESSMENT OF WHOLE BRAIN EPI IMAGING TECHNIQUES FOR FUNCTIONAL MRI

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1 QUANTITATIVE ASSESSMENT OF WHOLE BRAIN EPI IMAGING TECHNIQUES FOR FUNCTIONAL MRI A Howseman, D Porter, O Josephs and R Turner, Wellcome Department of Cognitive Neurology, Institute of Neurology, Queen Square, London WC1N 3BG Functional MRI (fmrl) of the human brain is based on a change in the NMR signal on T 2 * weighted images due to local changes in the concentration of deoxyhemoglobin during neural activity associated with the performance of a task. This is known as blood oxygenation level dependent (BOLD) contrast. If we wish to quantify these functional changes in image intensity we may use a scale of magnitude of signal change on a voxel by voxel basis. An alternative approach is to measure the magnitude of signal change and the variance in the data during the experiment and use these to generate a statistical image. The advantage of this approach is that the degree of physiological fluctuation in the data is taken into account when assessing the difference in signal level between two different functional states. The method of statistical parametric mapping (SPM) as developed by Friston and colleagues in our dept. is an advanced approach to generating functional brain images using PET or fmrl. The study of human cognition with fmri is best performed using whole brain imaging methods. Ideally data acquisition should also be as rapid as possible. Echo-planar imaging is the optimal technique to satisfy these requirements. Volumetric data can be acquired either by using multislicing or by incorporating a phase encode gradient in the 3rd dimension. We have implemented 3D phase encoded EPI and have assessed how its performance compares with the multislice method. We have also investigated what effect on the data the order and orientation of the slice selection has. A quantitative comparison between these data sets has been performed using SPM. All data were acquired on a 2T Siemens Vision scanner with matrix sizes of 64 x 64 x 64 and a FOV of 192mm. An echo time of 40ms was used and for both the 2D multislice method and the 3D version, volume acquisition took 5.44 sec. Flip angles of 15 0 and 30 0 were compared for the 3D experiments. The results showed up to a factor of 2 improvement in SNR for the 3D method. Qualitatively the two techniques yield very similar activation images. To assess whether there are improvements in the fmri data resulting from the increased SNR we generated histograms of the Z-scores of activated voxels. Our data suggest that there are potentially larger areas activated at a given threshold of significance but that the 3D method may be more susceptible to system stability and subject motion. We compared the multislice data in which the slice order was changed and found that there were very few significant differences at the p=0.01 level between them. An important potential application of fmri is in repeated studies over time of patients receiving treatment for neurological diseases. Preliminary data from a study on how reproducible the fmrl data is in the context of repeated measurements on the same subject in different sessions will be shown. The effect of subject position in the scanner and of MRI system calibration on the data has also been studied. A simple passive viewing task has been used in all of these experiments. This is chosen because it is the type of experiment which should be least susceptible to psychological variability Quantitative MRI Session 4

2 DEVELOPMENT AND IMPLEMENTATION OF AN AUTOMATED QUALITY CONTROL SYSTEM FOR FUNCTIONAL MRI EA Moore 1,2, A Simmons 2,3,4, SCR Williams 3,4, 1 Dept of Medical Engineering & Physics, 2 Neuro-imaging Dept, King's College Hospital, Denmark Hill, London SE5 9RS, 3 Neuro-imaging Dept, The Maudsley Hospital, DeCrespigny Park, London SE5 and 4 Neuro-imaging Research Group, Institute of Psychiatry, DeCrespigny Park, London SE5 Introduction: BOLD contrast fmri studies may be badly affected if small signal changes due to neuroactivation are compromised by system drifts, changes in S.N.R. and artefacts. A robust fmri quality control (Q.C.) acquisition protocol and automated analysis system has been designed to monitor these parameters for two fmri systems. Methods: Single shot T 2 * weighted gradient echo echoplanar images are initially acquired in three orthogonal planes. Three temporal datasets are subsequently acquired using a standard (five minute period) fmri protocol. Data is automatically analysed using custom written software, generating information relating to S.N.R., ghosting and system drift (including maximum signal change within a temporal dataset). The data is automatically compared to previous results and the operator is alerted to statistically significant changes. Typical Results Signal to Noise (S.N.R.) Signal to Ghost (S.G.R.) Max. Signal Change Axial (R/L) Axial (A/P) Axial (R/L) Axial (A/P) Near-Axial System % System % Both systems show high S.N.R. but S.G.R. in system 1 is five times greater than system 2. The maximum signal change in system 2 is greater than that observed in more subtle paradigms. Discussion: The programme provides an early alert to reduction in system performance and a more sensitive indication of hardware faults than a standard Q.C. programme. This is extremely important in serial fmri studies and fmri studies involving very small signal changes, thus we advise that objective QC measures are reported in fmri publications. Such measures can also be used to determine suitability of specific systems for fmri Quantitative MRI Session 4

3 ASSESSMENT OF REGIONAL CEREBRAL BLOOD FLOW USING DYNAMIC CONTRAST-ENHANCED MRI IMAGES AL Martel and AR Moody 1, Department of Medical Physics, Queen's Medical Centre, Clifton Boulevard, Nottingham, NG7 2UH and 1 Department of Academic Radiology, University Hospital, Nottingham. It is possible to obtain information about brain blood flow from dynamic contrast-enhanced MRI images. The most common method of analysing such data is to produce a parametric image showing the estimated rcbv (regional cerebral blood volume) for each pixel. If the arterial input function is available then it is also possible to quantify the absolute rcbv and rcbf (regional cerebral blood flow). Both are necessary for an adequate characterisation of brain haemodynamics. Parametric images of rcbf are rarely generated, however. This may be due to the instability of the deconvolution technique generally used to calculate rcbf if the pixel time activity curves are too noisy. We have developed instead the following technique which allows us to generate functional images, with pixel values which are proportional to the rcbf. A series of T1 weighted images were acquired from 2 slices, through the level of the lateral ventricles and the carotid arteries respectively. Contrast was injected approximately 15 seconds after the start of image acquisition. The brain images were registered and noise was reduced by performing a principal component analysis on the data. We used Peters' (1987) method for measuring blood flow as this technique is more robust in the presence of noise than deconvolution analysis. Parametric images showing relative rcbv and time to peak have also been generated. This technique has been applied to more than 40 patients with a number of different conditions including stroke and carotid occlusion. SPECT images were obtained for 20 of the stroke patients and these showed good visual correlation with the perfusion images. It has been found that in general the rcbf images provide useful and complimentary information to the rcbv images. AM Peters, l987, Nucl. Med. Comms, 8: Quantitative MRI Session 4

4 CSF FLOW MEASUREMENT PRE AND POST SURGERY IN CHIARI MALFORMATION EA Moore, J Gill & JS Millar, Departments of Medical Physics, Neurosurgery & Radiology, Southampton University Hospitals NHS Trust, Tremona Road, Southampton S016 6YD The management of patients with hind-brain abnormalities presents a problem to neurosurgeons, since it is difficult to predict which patients will benefit from surgery. Recently it has been suggested that studying CSF flow at the foramen magnum may help resolve this problem. We have used a research sequence which produces gated phase-contrast images with a segmented k-space acquisition. Scans take only half the time of conventional PC sequences, and are able to use several signal averages, improving the signal-to-noise ratio. Two groups of subjects were scanned; 12 volunteers with normal anatomy, and 13 patients with a range of hind-brain abnormalities. Of the latter group, 2 had a repeat scan after decompressive surgery. The velocity of the CSF was measured at various points around the foramen magnum. In the cervical sub-arachnoid space in normal subjects, we measured a mean peak velocity of 22mm s -1 caudally, the peak occurring approximately 230ms after the R wave. In patients, the mean peak velocity was 53mm s -1 just below the foramen magnum and occurred earlier in the cardiac cycle, approximately 175ms after the R wave. In patients who were scanned postoperatively the peak velocities in this region were reduced from the pre-surgical values, and the peaks occurred much later in the cardiac cycle. We hypothesise that this is due to the large reservoir of CSF created below the cerebellum, which appears to 'damp' the pulsatile flow through the foramen magnum Quantitative MRI Session 4

5 MICRO-STRUCTURAL QUANTITIES - DIFFUSION, MAGNETISATION DECAY, MAGNETISATION TRANSFER AND PERMEABILITY MA Horsfield, Division of Medical Physics, Leicester Royal infirmary, Leicester LE1 5WW Conventional proton-density, T1- and T2-weighted magnetic resonance imaging methods are sensitive to the water content and the mobility of water molecules in tissue. Loss of tissue structure generally leads to increases in all three parameters in a way which is nonspecific to the pathological process. Several quantitative MRI techniques have been proposed which may be more specific to the underlying pathology, and may be interpretable as a particular aspect of tissue structure. These include magnetisation transfer imaging (MTI) (1), transverse magnetisation decay analysis (2), diffusion imaging (3) and contrast agent transport (4). MTI uses extra radio-frequency pulses set some way from the Larmor frequency of water: these pulses only directly affect the broad resonance lines assiciated with large (MRIinvisible) macromolecules. However, if there is transfer of magnetisation by an exchange process between the macromolecule and tissue water, then the net magnetisation of the visible protons is also reduced. Thus, MTI can show the presence or absence of macromolecules and, in brain tissue, efficient exchange is thought to be a marker particularly for myelin. The analysis of magnetisation decay curves has been around for many years (5). However, the collection of multiple echo images using whole-body MRI equipment is still technically very demanding. With a Carr-Purcell-Meiboom-Gill type pulse sequence, many echoes are needed in order to discriminate between the different time constants for transverse relaxation and there are many potential sources of artefact when imaging methods are emloyed. With careful set-up, it is now possible to discriminate between the relaxation times of intra-cellular and extra-cellular tissue water (2). MRI diffusion techniques are sensitive to the root mean square (RMS) displacement of the water molecules they follow in a random (Brownian) course within the tissue. All techniques measure the apparent diffusion coefficient (ADC) of water, since the presence of permeable or non-permeable barriers (such as cell membranes) hinder the free motion of the water. Destruction of the barriers, or changes to the geometry or permeability of the barriers leads to changes in the apparent diffusion coefficient. Diffusion MRI also has the unique property that the hindrance of free molecular diffusion reflects the orientation and anisotropy of the tissue which presents the barriers to motion. In some disease states, the normal transport of fluid is disturbed: for example in multiple sclerosis the blood-brain-barrier may be broken in areas of acute disease activity; in acute myocardial infarction the blood supply to the heart is reduced. The dynamics of transport in blood vessels or across barriers space are accessible using MRI contrast agents and a T1- weighted and T2*-weighted pulse sequence.(4) -18-

6 This paper will review the implementation and application of these newer quanititative MRI methods. References: 1. RS Balaban and TL Ceckler, Magnetization Transfer Contrast in Magnetic Resonance Imaging. Magnetic Resonance Quarterly, 8, (1992) 2. AL MacKay, KP Whittall, J Adler, DKB Li, D Paty and DA Graeb, In Vivo Visulaisation of Myelin Water in Brain by Magnetic Resonance. Magnetic Resonance in Medicine, 31, (1994). 3. PJ Basser, J Mattiello and D LeBihan, Estimation of the Effective Self-Diffusion Tensor from the NMR Spin Echo. Journal of Magnetic Resonance Series B, 103, (1994). 4. PS Tofts, Modelling Tracer Kinetics in Dynamic Gd-DTPA MR Imaging, Journal of Magnetic Resonance Imaging, 7, (1997). 5. RM Kroeker and RM Henkelman, Analysis of Biological NMR Relaxation Data with Continuous Distributions of Relaxation Times. Journal of Magnetic Resonance, (1986). -19-

7 ANISOTROPIC DIFFUSION-WEIGHTED IMAGING OF ISCHAEMIC STROKE PA Armitage, M Bastin and I Marshall, Department of Medical Physics, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU Diffusion-weighted imaging (DWI) allows the early detection of ischaemic tissue. Here we present results from a study of 26 patients presenting with acute ischaemic stroke. DWI was implemented on a 1.5 T clinical scanner (Siemens 63SP Magnetom) equipped with conventional gradients (10mT/m, 1ms rise time). Diffusion sensitivity was achieved with two gradient pulses of magnitude G=9.64mT/m, duration δ= 51ms and separation = 57.4ms, placed symmetrically around the first 180 RF pulse, in a conventional SE pulse sequence (TE=121ms), to give a b-value of 700s/mm 2. Motion artifacts were corrected using navigator echoes (TE=152ms). Transverse images were obtained with diffusion gradients applied in three orthogonal directions, corresponding to left-right (x), anteriorposterior (y) and head-feet (z) directions. 67% of the 672 DWI's obtained were judged to be acceptably free from artifact. ADC trace and anisotropy images were calculated. Region of interest measurements were obtained, from small cortical and lacunar infarcts, as well as contralateral normal regions. This data is summarized in figure 1. The DWI's obtained with diffusion gradients in the z-direction generally show more artifact, which agrees with the limitations of the navigator correction technique. The results for the ADC s agree with those previously reported and show a decreased value in stroke regions. The anisotropy is shown to be increased in stroke regions, possibly due to the increased tortuosity of the extracellular water caused by cell swelling. FIG. 1 Stroke Normal ADC (x10-3 mm 2 s -1 ) Anisotropy* *Anisotropy is scaled such that 0 represents isotropy and 1 represents complete anisotropy. -20-

8 MONITORING EFFECTIVENESS OF INTRA- ARTICULAR TREATMENT OF RHEUMATOID ARTHRITIS OF THE KNEE USING QUANTITATIVE ANALYSIS OF DYNAMIC Gd-DTPA MRI A Radjenovic 1, JP Ridgway 1, PJ O'Connor 2, WW Gibbon 2, E Berry 1, JC Waterton 3, R Maciewicz 3, 1 Departments of Medical Physics and 2 Radiology, University of Leeds, Department of Medical Physics, Leeds General Infirmary, The Wellcome Wing, Gt George Street, Leeds, LS1 3EX and 3 Department of Vascular Inflammatory Musculoskeletal Research, Zeneca Pharmaceuticals, Alderly Park The earliest subclinical changes in rheumatoid arthritis (RA) involve a change in synovial microcirculation. Dynamic Gd-DTPA enhanced MRI (DMRI), with its ability to evaluate those changes, has a strong potential for objective and reliable treatment progress monitoring. Eight patients with symptomatic involvement of one or both knees were examined before and after treatment with triamcinolone acetonide (TA, n=6) or TA + 200MBq Yttrium90 (TA+Y90, n=2). MRI scanning was performed using a Siemens Impact 1.0T. [2D-FLASH TR/TE/ϕ = 45/6/90 ]. Quantitative analysis of Signal Intensity/Time curves was performed using software developed in C programming language. Pixel-to-pixel analysis was performed on a subset of data encompassing the joint capsule. SI/Time curves were quantified in terms of Initial Rate of Enhancement (IRE), Maximal Enhancement (ME) and pharmacokinetic parameters k 21 (fractional transfer rate constant between the plasma and extracellular space) and A (Gd-DTPA availability factor, related to the volume of the extracellular space and pre-contrast T1). An open two-compartment model of Gd-DTPA kinetics was used for extraction of pharmacokinetic parameters. Normal probability statistics was used for evaluation of histogram migration (two-tailed Z- test for the difference of the means). In all 8 patients a significant (p<0.05) reduction in the IRE and k21 was detected indicating reduction in capillary permeability. There was also a significant (p<0.05j reduction in ME and A in patients treated with TA. However, patients treated with TA+Y90 showed a significant increase in A, suggesting an increase in the volume of the extracellular fluid. These results clearly indicate that quantitative analysis of DMRI can objectively measure treatment induced changes in RA. -21-

9 MEASURING CAPILLARY PERMEABILITY USING DYNAMIC Gd-DTPA UPTAKE CURVES PS Tofts, Institute of Neurology, University College London, Queen Square, London WC1N 3BG Dynamic Gd-DTPA MRI is carried out in many tumour types, in disruptions of the Blood- Brain barrier such as multiple sclerosis, and in the leaking retina. The enhancement of signal intensity (SI) depends on many factors; MR factors such as the dose (its magnitude and duration), the sequence type and parameters, the field strength, and tissue parameters (T1, permeability, extracellular space and possibly perfusion). Several models of the SI vs. time curve have been proposed, in attempts to characterise the tissue independently of the MR and injection protocol. These have been analysed and reconciled in a unified view (1). A model by Tofts and Kermode (2) estimates permeability K PSρ (actually the PS product per unit volume of tissue), and the extravascular extracellular space (EES) v e. The T1 of the tissue before injection of tracer must be known. Other models estimate k ep, the efflux rate constant from the EES to the plasma, which is less physiologically specific, since k ep = K PSρ /v e. Permeability and EES have been estimated in multiple sclerosis, breast tumours and retinal leaks. In the latter, measurements were validated by extraction of the vitreous. Practical issues remain to be solved: should the arterial plasma concentration be measured or modelled? What T1- weighted sequence should be used? How applicable is the model to flow-limited situations such as tumour vasculature? The method has potential to characterise quantitative physiological tissue parameters in a routine clinical measurement, to monitor the progress of disease and its response to therapy, independent of the particularly MR scanner and sequence used. References: 1. Modelling tracer kinetics in dynamic Gd-DTPA MR imaging. PS Tofts, JMRI 7: (1997). 2. Measurement of the Blood-Brain Barrier permeability and leakage space using dynamic MR imaging - 1 Fundamental concepts. PS Tofts & AG Kermode, Magnetic Resonance in Medicine 17: (1991). -22-

10 QUANTITATIVE MAGNETIZATION TRANSFER IMAGING NP Davies, P Collier, IR Summers, W Vennart, Department of Physics, University of Exeter, Stocker Road, Exeter, Devon EX4 4QL Magnetization Transfer (MT) imaging exploits the continual exchange that takes place between macromolecular protons and mobile water protons in many biological tissues. In MT imaging the macromolecular protons, which have a short T 2 relaxation time compared to the "free" protons, are selectively saturated. The magnetization of the "free" protons available to produce signal in a subsequent imaging sequence is then reduced in proportion to the amount of exchange taking place. For clinical systems two suitable methods of selective saturation of the macromolecular protons involve pulsed off-resonance and pulsed on-resonance sequences. In offresonance methods gaussian or sinc shaped RF pulses are applied at some frequency offset from ω 0 such that the "free"-water resonance is unaffected while the macromolecular protons are excited. On-resonance methods involve applying composite pulses that have a null at ω 0 in their frequency spectrum. Commonly, binomial pulses are used in which the lobe durations are governed by a binomial series of a particular order. On-resonance binomial pulse MT sequences have been shown to be more efficient than off-resonance methods. Our investigations of binomial pulse sequences have revealed the importance of accurate setting of the binomial pulses in order to avoid image artefacts, and to produce reliable quantitative results. Reproducibility of MT results depends on uniformity of the B 0 and RF fields, consistency of subject repositioning, stability of the RF amplifiers, and on system noise. The final source of variability is physiological changes, which can be quite marked in muscle tissue for example. Quantitative MT measurements have been applied to the lower-leg muscles in a study of venous leg ulcers. These results showed a reduction of MT Ratio of the muscle in the disease state, and a general reduction of MT Ratio of muscle with age. -23-