The role of magnetic resonance spectroscopy in clinical medicine

The role of magnetic resonance spectroscopy in clinical medicine

Magnetic Resonance Imaging. Vol. 3, pp. 407413, Printed in the USA. All rights reserved. 073&725X/85 $3.00 + .OO Copyright 0 1985 Pergamon Press Ltd...

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Magnetic Resonance Imaging. Vol. 3, pp. 407413, Printed in the USA. All rights reserved.

073&725X/85 $3.00 + .OO Copyright 0 1985 Pergamon Press Ltd.

1985

l Continuing Education THE ROLE OF MAGNETIC RESONANCE SPECTROSCOPY IN CLINICAL MEDICINE PETER J. BORE Clinical Director, M.R.C. Clinical NMR Facility, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, England This article presents a view which emphasises the particular perspective of a clinician who has close involvement in magnetic resonance spectroscopy (MRS) and is directed towards readers who wish to understand the likely role of MRS in clinical medicine. Many more complete reviews already exist, including two review articles from our group. Another review would hardly be justifiable and those readers seeking such an article should consult Refs. 1-5. This will be more in the nature of a personal overview of the topic and one which will touch upon some of the problems which accrue from the interactions of scientists with little appreciation of clinical medicine with clinicians who have little understanding of the complexities of the NMR experiment. Moreover, the discussion will he confined to situations where MRS is likely to impinge directly on problems of day-to-day clinical management, as opposed to situations where the results of MRS research lead to an improved understanding of particular disease states, but where there is no need for each and every patient who is a potential benificiary of the technique to undergo an MRS examination.

INTRODUCTION

relevant to diagnosis and management would be found wanting if it were judged on criteria of scientific validity. Conversely, much that is scientifically proven about man and his diseases has not yet found any application in the prevention or treatment of his ailments. The principles of NMR are simple. The technical complexities of the experiment, like the flux distribution of a surface coil or the influence of pulse sequence on signals obtained, are formidable. There is a real problem in communicating the uncertainties of NMR data to those not conversant with these complexities. At this stage one might reasonably ask what clinical applications are scientifically proven. The answer is “very few.” There are many variables in the NMR experiment and in human studies it can be very difficult to maintain complete control over them all. Most of the artefacts of which I am aware were discovered rather than predicted. Virtually all clinical MRS experiments have assumed that spin-spin and spin-lattice relaxation times of phosphorus are unchanged during exercise or as a result of pathology. Given the difficulty or even impossibility of measuring relaxation times in the context of clinical studies it is probably the best assumption we can make, but it is

In trying to gain an understanding of what MRS can do in clinical practice or clinical research we must make some clear distinctions in our thinking regarding those things which are proven beyond scientific doubt, those which are proven on the basis of certain assumptions and those things which it seems will, in the fullness of time, prove to be the case. It is the second category which tends to cause problems. It is all too easy to make what are very reasonable assumptions in order to interpret data and then perhaps use these conclusions in another situation, forgetting that they were dependent on, and are no more valid than, the initial assumptions. Moreover, it is not always possible for a third party to discern what assumptions have gone into some of the conclusions which are presented. In dealing with clinical data we find ourselves in difficult territory, where on the one hand we must take care to ensure that conclusions based on assumptions are not passed on to clinical colleagues as proven and immutable fact, and yet on the other hand we must remember that clinicians frequently deal with uncertain data and rarely make decisions on the basis of single items of information. Much that is clinically

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nevertheless an assumption-not a scientific fact. And if it is eventually demonstrated that there are indeed substantial changes in relaxation times then the numerical interpretation of some of our data would need modifying. It must be said that to make much difference the relaxation rate changes would have to be improbably large, but improbably large is not synonymous with impossible. Therefore it seems that most, if not all, clinical MRS experiments are based at some point on at least one assumption, and without being intimately acquainted with the experiment, the manner of data accumulation, processing and interpretation it is impossible (even for an NMR expert) to deduce from many existing scientific papers exactly wlIat assumptions have been made to reach the stated conclusions. Thus we are perhaps reduced to asking two questions: (1) what has MRS offered to clinical medicine so far, accepting that assumptions, most of them reasonable but some of them unknown, have had to have been made and (2) what considerations influence our guesses about potential clinical applications of NMR. MAGNETIC

RESONANCE

SPECTROSCOPY

It is perhaps appropriate to remind those readers who are only familiar with magnetic resonance imaging (MRI) of the salient features of MRS. Like MRI it depends on the relationship between magnetic field strength and the precessional frequency of the observed nuclei. In MRI a field gradient is applied to induce nuclei at different points in space to precess at different frequencies. Thus position is encoded as frequency and the frequency of a signal enables it to be assigned as originating from a particular point in space. In MRS frequency encodes not the position of the nucleus but the nature of the molecule of which it is a constituent. The other components of the molecule screen, to a greater or lesser extent, the nucleus from the applied magnetic field. Thus the field which the nucleus perceives will vary depending on what molecule it is a part of, and its precessional frequency will likewise vary. When the data is analyzed the different frequencies collected can be ascribed to nuclei in particular molecules. A biological phosphorus spectrum is shown in Fig. 1. It is in fact a spectrum of the author’s brain. It will be recalled that NMR is not a particularly sensitive analytical method largely because of the unfavourable numbers which emerge from the Boltzmann distribution.2 Thus, only phosphorus metabolites which are present in concentrations of the order of a millimolar or more can be identified. The spectrum shown reveals peaks arising from inorganic phosphate (Pi), phosphocreatine (PCr), ATP, phospho-diester and sugar phos-

d

Fig. 1. A phosphorus-3 1 spectrum of brain. (a) Sugar phate, (b) inorganic phosphate, (c) phosphodiester, (d) phocreatine, (e) alpha ATP, (f) gamma ATP, (g) beta The position of the inorganic phosphate peak indicates of 7.08.

phosphos-

ATP. a pH

phate. Additionally, we can deduce from the frequency of the inorganic phosphate signal the pH of its environment. It must be admitted that within the totality of human biochemistry this is a very small amount of information. However, it must be remembered that virtually all cellular activities depend an ATP for their source of energy. Figure 2 shows the three principal methods whereby ATP can be produced: by the breakdown of phosphocreatine, by glycolysis and by mitochondrial oxidative phosphorylation. We are fortunate in that phosphorus MRS can yield information about all three of these methods of ATP production. The amount of phosphocreatine in the sample can be estimated directly from the spectrum with a time resolution which may vary from several seconds to lo-20 min. Glycolytic ATP production is accompanied by the production of lactic acid and therefore a fall in pH. Since pH can be measured we have here an index of glycolytic activity when allowance has been made for the export of protons from the PCr

oxidativc phosphorylation

glycolysis II

\

ATP

ADP

+Pi+

energy

Fig. 2. Energy supply in the cell

MRS in clinical medicine 0 PETER J. BORE

cell and for their incorporation in other metabolic pathways. Finally, it is possible to derive information about mitochondrial activity. This is discussed in detail elsewhere6 but in its simplest form consists of measuring PCr regeneration after it has been depleted by exercise. Under these circumstances the only process contributing to energy production is mitochondrial oxidative phosphorylation and thus the rate of PCr resynthesis is a measure of mitochondrial activity. MRS has offered the following to clinical medicine to date. Identi’cation of disorders of glycolysis Several defects can exist in the pathway through which glycogen is broken down to produce lactate, protons and ATP. Normal subjects produce lactate and protons during moderate exercise which, at least for some of the time, exceeds the rate at which protons can be consumed or exported.7 In consequence the intracellular pH falls. In our standard exercise protocol, which has been selected such that it is readily carried out by patients who may be neither well motivated nor have particularly strong muscles, the pH falls during exercise by about 0.5 pH units. Failure to acidify is readily detected and if it persists at higher work loads or under anaerobic conditions (tourniquet ischaemia) is undoubtedly abnormal. If it is available MRS is probably the method of choice for excluding defects in glycolysis since the ischaemic lactate test is uncomfortable and invasive, and unless performed with some care subject to spectacular false-positive results. Of course MRS examinations need performing and interpreting with some care and are far from trivial in their requirements of personnel and equipment. An ischaemic lactate test requires no more than a syringe, a tourniquet and the routine hospital biochemistry service. Some inferences about the site of the block in glycolysis may be obtained, as exemplified by the appearance of large amounts of glucose-lphosphate during exercise in phospho-fructo-kinase deficiency,8 but at present if MRS does reveal a defect it is usually necessary to proceed to muscle biopsy and enzyme analysis to identify the site of the lesion with precision. Mitochondrial lesions The situation is broadly similar for mitochondrial lesions. A number of NMR abnormalities have been identified6 in these subjects, including alterations in resting values of PCr, Pi, ADP, and pH, more rapid utilisation of PCr during exercise and delayed recovery of PCr and ADP when exercise ceases. Again MRS is more of a screening test, and conventional methods are usually employed to accurately localise the biochemi-

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cal defect. A further limitation of MRS in this area is that as yet it is not clear what magnitude of defect must be present for it to be detectable. More MRS studies on patients who have been fully investigated by conventional methods should help to resolve this problem. Changes in Duchenne muscular dystrophy Changes have been demonstrated in Duchenne muscular dystrophy in a group of boys with advanced disease.’ The changes consist of altered metabolite ratios, high pH, and the presence of a compound not normally seen in forearm muscle. While this group of changes has not been seen in other conditions to date, each of the individual components have and thus their diagnostic and pathological significances are unclear. It is not yet known if changes can be seen using MRS at a stage in the disease when the clinical diagnosis might be in doubt. Evidence of birth asphyxia Studies on the brains of neonates have indicated that evidence of birth asphyxia is sometimes available from MRS investigations and that in general it has some prognostic value.” Intermittent claudication Work has been reported showing changes in the metabolism in the legs of patients suffering from intermittent claudication. Initially leg studies were carried out on a 20 cm bore magnet.” Recently it has become possible to carry out investigations in a wholebody magnet,” thus enabling the subject to be studied at rest, during a period of exercise and throughout the subsequent recovery phase. Results to date are promising in that they are in keeping with the anticipated biochemical changes (rapid utilisation of PCr stores and slow recovery after exercise) and there is some correlation between the NMR findings and the severity of the patients’ symptoms. On the other hand, NMR has not yet improved on any of the existing methods for assessing or investigating peripheral vascular disease, and therefore its future in this area must depend on advances still to be made. Persistent exhaustion/fatigue An unexpectedly interesting group of patients are those who suffer from persistent exhaustion/fatigue following viral infections. Many aetiologies have been ascribed to this symptom complex and frequently it has been concluded that these patients have a functional disorder. On NMR examination some, though not all, have a characteristic deviation from normal in the relationship between the utilisation of phosphocreatine

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and the accumulation of protons during exercise, suggesting that there may be some disorder of metabolic control.2.‘3 It is not clear whether further investigation by NMR is appropriate or what the diagnostic significance is since not all “postviral fatigue” patients show these metabolic changes. Only if the underlying defect can be identified and some therapeutic measure devised will MRS have significant impact in this disorder. Nevertheless it has been some consolation to a few of our patients to learn that they do have an objectively demonstrable anomaly when they have previously been accused of malingering, and these findings have provided some additional incentive to those who have been studying this condition using other techniques. Hypothyroidism In addition there are several findings exemplified by the observation of an additional peak in the phosphodiester region of the spectrum in the forearms of the majority of hypothyroid patients so far studied.3,4 This peak regresses after treatment with thyroxine. At present this remains an interesting feature which raises a number of questions but which is without clinical significance.

POTENTIALS

OF MRS

It will be apparent from the above that the uses of MRS in clinical medicine are very restricted. Few conditions have been studied and where positive findings have emerged the diseases are often rare and MRS has not replaced conventional investigative methods. So far MRS has not led to improved treatment. However, it must be recognised that much of the research effort to date has gone into the development of techniques and equipment and much effort will continue to be expended in these directions. Only muscle disorders have been extensively studied. The potential usefulness of MRS in most situations is as yet unexplored in any formal way. Thus we come to the second of our questions: What will the potential prove to be and how easily and quickly will it be realised? An intimate knowledge of MRS does not seem to be of great help in producing answers to those questions, since that knowledge serves primarily to increase the number of variables and uncertainties which one takes into consideration. Thus almost any appraisal of these questions is little more than guesswork, and the guesses to date have come principally from three sources: clinicians who are interested in using MRS, scientists who wish to develop the clinical applications of MRS and finally the manufacturers of NMR equipment. This latter group clearly has a very significant axe to grind,

0 Volume 3, Number

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though it is perhaps also true that in the long term they have the most to lose by making rash predictions to their customers and giving them unreasonable expectations as to what the equipment will be able to do. Also, they should be the most able to comment on what technical developments are just around the corner. Perhaps the most general criticism that can be made of manufacturers is that they have, perhaps unwittingly, tended to play down the difficulties of human MRS experiments at the clinical level, though I think that recently I have sensed a more realistic air developing. The traditional objectivity of the scientist can be difficult to maintain when he is called upon to comment about clinical medicine, a subject about which his knowledge is limited and which is often, by force of circumstance, practised in a manner which is neither objective nor scientific. The pressures on the clinician, the uncertainty of much of the data he uses, and the nuances which contribute to his decision making can seem almost mystical to the uninitiated, and there can be considerable problems in communicating to the scientist the lack of objective scientific precision which is quite frequently inherent in the conclusions of the most meticulous physician-conclusions which may have the most profound significance for his patient. Even some of the “hardest” clinical data, for example those which we get from the histopathologist, often contains a considerable element of subjective interpretation. While it is true that clinicians crave for objective data on which they can base decisions it is also true that even the best data will be relegated to being but a factor which is added to one side or the other of the balance of clinical judgment. The third source of comment comes from clinicians. Few of these have had practical experience of MRS and ever fewer of MRS being applied to humans. It is less than satisfactory that so much has appeared in print and has been delivered at lectures concerning the undoubted advantages of MRS when the problems and limitations of the technique are virtually never discussed. Many have, I fear, been seduced by the concept of “noninvasive in vivo biochemistry” and have heard little about the relatively limited range of indentifiable compounds, the problems of sensitivity, the cumbersome nature of the experiment and the uncertainties of data analysis which are part and parcel of human MRS in 1985. 1 would suggest that for MRS to find a significant role in the day-to-day management of patients (as, say, x-rays have) it is necessary for the technique to advance to the point where it can produce the following: 1. 2. 3. 4.

a spectrum, without undue risk to the subject, in a reasonable time, with adequate signal to noise,

MRS in clinical medicine l PETERJ. BORE

5. 6. 7. 8. 9. 10.

with adequate spectral resolution, which can be interpreted qualitatively, which can be interpreted quantitatively, which is reproducible from subject to subject, which is reproducible from day to day, which is derived from a known anatomic location, 11. which is derived from a homogeneous anatomic location, 12. and which yields results with a variability which allows the identification of pathological states. One might add that all this needs to be achieved at acceptable cost and without requiring expertise which is so scarce as to be practically unobtainable. I would suggest that we are now about halfway through this list, and that in specific circumstances like muscle studies we can fulfill all these conditions but that in most other situations we can only add some of the items from the second half of the list. What then of the future? The achievements so far certainly justify a number of institutions using MRS for clinically orientated research purposes. Ultimately MRS could have a greater impact on medicine by what it contributes to our basic understanding of pathophysiology, thus enabling us to logically devise improved treatment, than by its use as a routine tool for the diagnosis of disease or the monitoring therapy. Routine daily use of MRS will be limited for some time to come by its need of equipment which is expensive, novel, has fairly stringent siting requirements and which needs a considerable amount of expertise and experience for its operation. Even with this expertise MRS is still a relatively slow and cumbersome procedure and in most situations requires some degree of patient cooperation. Not infrequently examinations are frustrated by a patient’s inability or unwillingness to provide that cooperation. Overcoming these disadvantages is in part a matter of improved technology, some ingenuity and greater experience, but it would seem likely that to achieve anything approaching the description of “being a routine investigation” MRS must either find multiple applications in a wide variety of conditions in the way that x-ray studies have, or there must emerge a major role for MRS in an important single area of medicine (that is, important in that it has more than trivial consequences to individual patients and numerically important in terms of its prevalence in the community). An example of such a situation would be exfoliative cytology, which has had major impact in the management of cervical carcinoma but which finds relatively little application elsewhere. If, for example, there is eventual sustantiation of the suggestions that MRS will be able to identify tumours which will be responsive to, or which are

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actually responding, to chemotherapy or radiotherapy then a major area of application will have been uncovered and almost overnight there will be an orderof-magnitude change in the clinical utility of MRS. Another area of potential could be in the monitoring of zones of ischaemia (strokes, myocardial infarcts, ischaemic legs) to detect both natural progression or resolution or to gauge the response to therapy. The metabolic information gained about the ischaemic process could have prognostic value and may thus influence drug therapy or modify the timing and/or nature of surgical intervention, perhaps prompting an earlier decision to, say, amputate a limb and possibly indicating the most appropriate level of amputation. If changes could be demonstrated in cerebral oedema then MRS monitoring could lead to therapy being influenced by the metabolic status of the brain. Hepatic handling of phosphorylated sugars or of carbon- 13-labelled substrates could prove to be a sensitive indicator of hepatic dysfunction, as well as giving some indication of the site of metabolic derangement in some liver disorders. Decisions about the fate of transplanted tissues could be aided by some knowledge of its metabolic status. New potential applications continue to be developed. In this group recent papers submitted describe studies on liver and fat, both of which could lead to clinically useful procedures. This continual expansion of MRS techniques encourages one to believe that sooner or later significant clinical uses will emerge. That belief is not without some support. The many animal studies carried out in the last ten years give some insight into the potential capabilities of MRS. Many clinicians will be all too aware of the extremely limited information available to them when they have to make decisions about the treatment of patients with, for example, acute abdomens or myocardial infarcts. Relatively small amounts of data in these situations could be of great help in patient management, though of course most clinicians will also recognise that additional data may well serve only to add to the present confusion! Finally, one must remember the rapidity with which this technique has developed. I have been involved in MRS for only eight years. I did my first MRS experiment (in a state-of-the-art laboratory) in 1977 using a 2 cm bore magnet and samples of baby rat kidney only 8 mm in size.14 In the last eight years I have seen the introduction of larger and larger magnets leading to whole animal studies, and the use of implanted coils,‘5.‘6 surface coils” and field profiling.‘* Recent evidence suggests that steerable volume selection might be feasible, though it is not yet clear if a signal-to-noise ratio adequate for human studies will be achieved. By 1983 I had progressed with my samples from baby rat kidneys to intact humans.’ Given

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the progress of the last eight years it is not unreasonable to be guardedly optimistic about the next eight. Nevertheless, the possibility of our having reached a plateau must also be considered. Between the 1940s and the 1950s the maximum speed of aircraft increased by a factor of 4 from around 400 mi/hr to some 1600 mi/hr. The ensuing 30 years have seen travel at Mach 2 extended from the fighter pilot to the airline passenger, but there has been little increase in maximum speed, with military aircraft of 1985 vintage still limited to around twice the speed of sound. At the end of the day I can do little more than dodge the question of the likely role of MRS in clinical medicine. Having discussed some of the factors which would enter into such a prediction it is clear that on the one hand the potential clinical utility is enormous, and it could quite quickly become a technique which every hospital wanted. On the other hand, the uses which have emerged to date would hardly justify the expenditure and effort of acquiring an MRS installation purely for its use as a routine clinical tool. Somewhere between these two extremes lies the future of MRS. Knowing a little about the practical difficulties of carrying out MRS studies on humans, my guess is that it will be some years before we will know where between the two extremes actuality will prove to be. Finally, two interrelated aspects of MRS deserve mention: safety and ethics. Safety. Theoretical considerations lead one to believe that magnetic fields and low-power radiofrequency signals are unlikely to have harmful effects on biological tissues. This has unfortunately led to a number of oversimplified statements about the hazards of magnetic resonance examinations and an erroneous belief that the procedure is risk-free. The following hazards and potential hazards of magnetic resonance examinations should be familiar to anyone who has the responsibility for patients undergoing such examinations or anyone who undertakes to advise on the suitability of subjects for magnetic resonance studies. Problems due to ferromagnetic attraction: surgical or traumatic metallic implants, pacemakers, ferromagnetic projectiles.‘9-2’

Problems associated with a magnet quench: fear, asphyxia, induced currents due to the field decay.22 Radiofrequency heating.23-25 Induced currents due to changing$eld gradients.26 Induced voltages in moving conductors (e.g. blood) in a static magnetic jield.26 Postulated eflects due to magnetic orientation of macromolecules, enzyme kinetic changes caused by quenching of biological superconductivity, and modification of nerve conduction velocities.27 In addition, there is an extensive literature which claims to show harmful effects of magnetic fields.28~30 These include EEG changes, changes in blood cells, electrolyte changes, adrenal lesions, delayed wound healing, accelerated allograft rejection, foetal maldevelopement and reduced tolerance to anoxia. Also claimed is longer life, less hostility and more youthful appearance! While it is true that few of these studies would be regarded as proof of any effects, it is also true that few, if any, have been formally refuted. On balance it would seem that magnetic resonance will prove to be one of the safer methods of investigation, but it is clear that there are some hazards and a number of uncertainties. A degree of caution is appropriate. Ethics. Ethical considerations inevitably devolve, at least in part, from safety. MRI can frequently be justified, in the opinion of an expert and supported by objective evidence, as a procedure done in the expectation of providing benefit to the patient. In those circumstances there can be a tradeoff between the risks and benefits, as there is with many procedures in medicine. Only in a very small number of situations can MRS make similar claims, since most MRS examinations at present must be considered as research procedures done to either develop the technique or in the hope of establishing whether the examination will be of benefit to the present or subsequent patients. In this situation it is necessary to recognise and respect the more rigorous ethical and legal constraints which govern the obtaining of informed consent to procedures of a nature which is experimental rather than beneficial.3’

REFERENCES Radda, G.K.; Bore, P.J.; Rajagopalan, B.J. Clinical aspects of 31-P NMR spectroscopy. Br. Med. Bull. 40: I 55-159; 1984. Bore, P.J. Principles and applications of phosphorus magnetic resonance spectroscopy. H.Y. Kressel ed. Magnetic Resonance Annual 1985. Raven Press, New York; 1985:45-69. Radda, G.K.; Taylor, D.J. Clinical studies by 31 P NMR. Int. Rev. Exp. Pathol. 27:1-58; 1985. Iles, R.A.; Stevens, A.N.; Griffiths, J.R. NMR studies

of metabolites in living tissue. Progress in NMR Spectroscopy 15:49-200; 1982. 5. Evanochko, W.T.; Ng, T.C.; Glickson, J.D. Application of in vivo NMR to cancer. Magn. Reson. Med. 1:508534; 1984. 6. Arnold, D.L.; Taylor, D.J.; Radda, G.K. Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy. Annals of Neurology (in press). 7. Taylor, D.J.; Bore, P.J.; Styles, P.; Gadian, D.G.; Rad-

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da, G.K. Bioenergetics

8.

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of intact human muscle: A 31 P nuclear magnetic resonance study. Molec. Biol. Med. 1:77-94; 1983. Edwards, R.H.T.; Wilkie, D.R.; Dawson, J.M.; Gordon, R.E.; Shaw, D. Clinical use of nuclear magnetic resonance in the investigation of myopathy. Lancet 1:725730; 1982. Newman, R.J.; Bore, P.J.; Chart, L.; Gadian, D.G.; Styles, P.; Taylor, D.J.; Radda, G.K. Nuclear magnetic resonance studies of forearm muscle in patients with Duchennne dystrophy. Br. Med. J. 284:1072-1074; 1982. Hope, P.L.; Costello, A.M. de L.; Cady, E.B.; Delphy, D.T.; Tofts, P.S.; Chu A.; Hamilton, P.A.; Reynolds, E.O.R.; Wilkie, D.R. Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth aspyxiated infants. Lancet 2:366-370; 1984. Chance, B.; Eleff, S.; Bank, W.; Leigh, J.S.; Warnell, R. 3 1 P NMR studies of control of mitochondrial function in phosphofructokinase-deficient human skeletal muscle. Proc. Natl. Acad. Sci. USA 79~7714-7718; 1982. Hands, L.; Bore, P.J.; Galloway, G.J.; Styles, P.; Morris, P.; Radda, G.K. 31 P NMR of calf muscle in peripheral vascular disease. Proc. Sot. Mag. Res. Med. New York X:297-298; 1984. Arnold, D.L.; Bore, P.J.; Radda, G.K.; Styles, P.; Taylor, D.J. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaution/ fatigue syndrome. Lancet 1: 1367-l 369; 1984. Sehr, P.A.; Radda, G.K.; Bore, P.J.; Sells, R.A. A mode1 kidney transplant studied by nuclear magnetic resonance. Biochem. Biophys. Res. Commun. 771195-202; 1977. Bore, P.J.; Sehr, P.A.; Chan, L.; Thulborne, K.R.; Ross, B.D.; Radda, G.K. The importance of pH in renal preservation. Transplant. Proc 8:707-708; 198 1. Grove, T.H.; Ackerman, J.J.H.; Radda, G.K.; Bore, P.J. In vivo analysis of rat heart by phosphorus nuclear magnetic resonance. Proc. Natl. Acad. Sci. USA 77~299-302; 1980. Ackerman, J.J.H.; Grove, T.H.; Wong, G.G.; Gadian, D.G.; Radda, G.K. Mapping of metabolites in whole animals by 31 P NMR using surface coils. Nature 283:167-170; 1980.

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18. Gordon, R.E.; Hanley, P.E.; Shaw, D.; Gadian, D.G.; Radda, G.K.; Styles, P.; Bore, P.J.; Chart, L. Localisation of metabolites in animals using 31 P “topical magnetic resonance.” Nature 287:736-738; 1980. 19. New, P.F.J.; Rosen, B.R.; Brady, T.J.; Buonanno, F.S.; Kistler, J.P.; Burt, CT.; Hinshaw, W.S.; Newhouse, J.H.; Pohost, G.M.; Taveras, J.M. Potential hazards and artifacts of ferromagnetic and non-ferromagnetic surgical and dental materials and devices in nuclear magnetic resonance imaging. Radiology 147:139-148; 1983. 20. Pavlicek, W.; Geisinger, M.; Castle, D.; Borkowski, G.P.; Meaney, T.F.; Bream, B.L.; Gallagher, J.H. The effects of nuclear magnetic resonance on patients with cardiac pacemakers. Radiology 147:149-153; 1983. 21. Bore, P-J.; Timms, W.E. The installation of high-field NMR equipment in a hospital environment. Magn. Reson. Med. 1:387-395; 1984. 22. Bore, P.J.; Galloway, G.J.; Styles, P.; Radda, G.K.; Flynn, G.F.; Pitts, P.R. Are quenches dangerous? 23. Bottomley, P.A.; Edelstein, W.A. Power deposition in whole body NMR imaging. Med. Phys. 8:510-512; 1981. 24. Bottomley, P.A. R.F. power deposition in NMR imaging. Proc. Sot. Mag. Res. Med. New York X163-65; 1984. 25. Brandt, G. Tissue heating by radiofrequency magnetic fields during magnetic resonance imaging. Proc. Sot. Mug. Res. Med. New York X:84-85; 1984. 26. Saunders, R.D.; Smith, H. Safety aspects of NMR in clinical imaging. Br. Med. Bull. 40:148-154; 1984. 27. Budinger, T.F. Nuclear magnetic resonance (NMR) in in vivo studies: Known thresholds for health effects. J. Computer Assisted Tomography. 5:800-8 11; 198 1. 28. Ketchen, E.E.; Porter, W.E.; Bolton, N.E. The biological effects of magnetic fields on man. American Industrial Hygiene Association J. 39:1-11; 1978. 29. Barnothy, M.F. Biological Vol. 1. Plenum Press, New 30. Barnothy, M.F. Biological Vol. 2. Plenum Press, New 31. Medical Research Council. tions on human subjects. Research Council 1962-63.

Effects of Magnetic Fields. York; 1964. Effects of Magnetic Fields. York; 1969. Responsibility in investigaReport of the Medical 1963:21-25.

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