MAGNETIC RESONANCE ZEUGMATOGRAPHY

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1 PAUL C. LAUTERBUR Deprtment of Chemistry, Stte University of New York t Stony Brook, Stony Brook, New York 11794, USA ABSTRACT Sptil resolution of mgnetic resonnce signls my be chieved by the use of vrious combintions of mgnetic field grdients. The experiments re exmples of new generl technique, 'zeugmtogrphy', by which imges my be formed by the use of induced locl interctions. Methods for the genertion of mgnetic resonnce imges of objects, including living orgnisms, re described, nd number of pplictions re illustrted nd discussed. INTRODUCTION Mgnetic resonnce techniques were originlly developed nd used to determine the properties of tomic nuclei nd to study the sttic nd dynmic interctions mong nuclei nd electrons in toms, molecules nd crystls. Such informtion on the properties nd behviour of mtter on the moleculr scle is most redily obtined if the sttic mgnetic fields responsible for the Zeemn splittings of nucler nd electronic spin energy levels re homogeneous, so tht the field vritions within the smples give rise to resonnce widths smll compred with the interctions being investigted. When the mgnetic field grdients imposed upon objects re lrge compred with the pek widths produced by intrinsic effects, the inhomogeneously brodened signls contin informtion on the sptil distributions of the nuclei or electrons t resonnce. Under these circumstnces, mgnetic resonnce becomes technique for studying structure bove the moleculr level" 2 When such experiments re combined with those in which moleculr properties re studied, the dt llow the sptil distributions of spectroscopic properties to be determined. GENERAL PRINCIPLES The experimentl techniques tht cn give rise to sptil resolution of resonnces re not, strictly speking, spectroscopic in nture. They depend upon the interction of mtter with rdition field in the presence of second field whose influence is function of lbortory sptil coordintes. The imge tht is generted represents the distribution, in the sptil coordintes determined by the defining field, of the entities tht couple tht field to the rdition field. The fundmentl principle involved suggested the generl nme 'zeugmtogrphy' for these techniques. It is derived from the Greek 'tht which joins together'. 149

2 PAUL C. LAUTERBUR Whenever the spectrl response of n object cn be mde dependent upon n inhomogeneous field, zeugmtogrphic experiment is possible in principle. Whether it is lso possible in prctice depends upon the ccurcy with which the effect of n pplied field grdient on pek shpes cn be distinguished from the intrinsic shpes nd from other distorting influences. Becuse mgnetic resonnce spectr often contin lines whose widths re much smller thn their frequencies, nd reproducible mgnetic field grdients re redily produced, mgnetic resonnce zeugmtogrphy is the most experimentlly convenient form of the technique, which permits the resolution of detil much smller thn tht theoreticlly distinguishble with rdio wves nd microwves if conventionl imging methods were used in homogeneous field. PRACTICAL CONSifiERATIONS Prcticl reliztion of these possibilities depends upon the development of pproprite combintions of experimentl pprtus nd techniques, s well s dt processing methods cpble of generting true imges from the results of ctul experiments. There re number of wys in which the effects of field inhomogeneities on mgnetic resonnce signls cn be used to produce useful pictures. All of them depend upon knowledge of the distribution of surfces of constnt mgnetic field within the object being studied. If the frequency of the spectrometer is swept, nd if ll prts of the object re eqully coupled to the rdio-frequency trnsmitter nd receiver coils, the integrted signl intensity t ech frequency will be the sum of the intensities from ll of the spins locted in the corresponding constnt field surfce. An especilly simple nlysis is possible if these surfces my be pproximted by fmily of prllel flt plnes perpendiculr to the grdient xis. The intensities then correspond to one-dimensionl projections perpendiculr to the grdient. Reltive rottion of the grdient nd the object bout n xis perpendiculr to the grdient genertes set of such projections, which cn be combined by imge reconstruction techniques4 to give two-dimensionl projected imge of the object s viewed from the direction of the rottion xis. Reltive rottions bout other xes will permit the genertion of other views, which cn be combined to give complete threedimensionl imge of the object in terms of its locl mgnetic resonnce signl intensities. If the surfces of constnt mgnetic field re not uniformly spced plnes, corresponding to the sme liner field grdient throughout the object, the plots of signl strength s function of frequency no longer correspond to simple liner projections, nd opticl nlogies nd imge reconstruction methods re not quite so strightforwrd. In rbitrry inhomogeneous mgnetic fields, generlized projections, defined s surfce integrls, my be used to construct imges if the shpe of the field cn be determined. The necessry one-dimensionl projections cn be obtined from frequency-sweep experiments, from field-sweep experiments or from trnsient experiments with pproprite Fourier trnsform or other dt processing to give plot of signl intensity s function of frequency. Ech will hve dvntges under certin circumstnces. The dt cn be mde to respond to relxtion time differences by performing progressive differentil sturtion 150

3 experiments or by perturbing the mgnetiztion with suitble pulses before observing free induction decy or echo in grdient. Imges produced from perturbed spin systems will contin informtion on quntities, such s the vrious relxtion times nd the locl diffusion coefficients, tht cn ffect the observed mgnetiztion under pproprite conditions. The simplifying ssumption tht the resonnce signl is single nrrow pek, identicl in ll prts of the object, will often be inpplicble to rel objects. The simplest wy to suppress the effects of pek shpes is to use grdient lrge enough for the entire pek to fll within one resolution element in the finl picture. For exmple, if the chemicl shifts in spectrum were to cover rnge of 500 Hz, sptil resolution of one prt in hundred would require tht the mgnetic field grdient over the object correspond to Hz. The chemicl shift informtion would then be filtered out of the dt nd only the distribution of the resonnt nuclei would be obtined from the imge. For those contributions to line shpe nd width tht re field-dependent, such s chemicl shifts nd internl demgnetizing fields, opertion t low mgnetic field will llow the use of smller grdients. When field-independent effects such s spin spin couplings re limiting, opertion t high mgnetic fields my often be desirble to give the highest possible signl-to-noise rtio. Zeugmtogrphic imging techniques re potentilly pplicble to wide vriety of mgnetic resonnce signls. Proton n.m.r. spectr of mobile tissue constituents other thn wter my be used, nd the signls of other nuclei will give pictures of their distributions, lthough signl-to-noise rtios will, of course, usully be much lower thn for wter protons in orgnisms nd their prts. The resonnces of solids cn be employed if the lines re nrrow, if lrge grdients re used or if line-nrrowing techniques cn be pplied5. ESR zeugmtogrphy is lso possible, nd should permit studies of the loctions of free rdicls nd prmgnetic ions within mterils nd complex structures, including biologicl objects. APPLICATIONS The condition tht the field inhomogeneity be much lrger thn the intrinsic spectrl width is most esily met in the nucler mgnetic resonnce spectr of liquids. The most common objects for which simple shrp resonnce is ccompnied by interesting structurl fetures re plnts nd nimls. Although the wter concentrtions nd relxtion times re different in vrious tissues nd orgns, most of the wter contributes to n pprently single strong proton resonnce. Reltively simple experiments in slightly modified n.m.r. spectrometers cn generte dt from which pictures of living orgnisms cn be constructed in terms of the concentrtion nd properties of wter in their tissues. A resolution of severl tenths of millimetre hs been chieved in experiments on wter in glss cpillries nd on smll clm, nd other objects up to bout 30 millimetres in dimeter hve been studied. The upper size limit is now set only by the vilble mgnet gp, nd much lrger objects could be exmined in n instrument with greter volume of homogeneous mgnetic field. NMR zeugmtogrphy my thus become generlly useful technique for the study of microscopic nd 151

4 PAUL C. LAUTERBUR mcroscopic biologicl structures, complementing the use of light, x-rys nd ultrsonic imging. EXAMPLES All of the exmples given here re from experiments in which n object ws scnned in conventionl n.m.r. spectrometer in the presence of field grdient lying in the plne of the receiver coil. Twelve different grdient orienttions were obtined by turning the object bout n xis perpendiculr to the direction of the min mgnetic field nd to the direction of the fixed field grdient. The 12 projections, tken 15 prt, were digitized nd were used by n itertive imge reconstruction progrm similr to 'multiplictive ART'6 to form 32 x 32 rry of intensities. Interpolted intensity vlues were displyed on line printer, using 16-level grey scle produced by vrious combintions of conventionl symbols. Some of the pictures hve been mde more plesing by photogrphic processing to improve contrst nd to suppress distrcting symbols by focusing djustments ' *<< Figure 1. Proton n.m.r. zeugmtogrm of two 1 mm cpillries of wter in 4.2 mm inside dimeter tube contining mixture of H20 nd D

5 ngure 2. Proton n.rn.r. zeugmtogrm of the wter distribution in pine brnch. The computer output hs been photogrphiclly filtered nd enhnced. 153

6 PAUL C. LAUTERBUR Figure 1 shows proton n.mr. zeugmtogrm of simple test object, two 1 mm dimeter glss cpillries of H20 in stndrd 4.2 mm inside dimeter smple tube contining mixture of H20 nd D20. The resolution, bout 0.2 mm, ws limited by grdient distortions nd by the use of only 12 grdients. A Vrin A-60 spectrometer, with extr field grdient controls, ws used for these experiments, which employed grdients of less thn 10 st cross the smple. Figure 2 shows the wter distribution inside conifer brnch bout 20 mm in dimeter. The smple ws surrounded by ir, nd ws held, inside tube with n inside dimeter of 28 mm, in specil cross-coil probe operting._,"-4 I.. I t ;.,,.Lc&srpectsØtcuLLrLrz:fl>>>.4c,t-..., I, I. zzx)' * * *CC>1CguQLc*.... *I>C*Ct'.*tc)cj I t>cdl.ic+t'..'%..'+ 2L0.D I,flflStscl;LCt*..'%'...,. C...xC*.p.,.%.*t<c,()CIIOCc MSeM&'xI,.c.t-..-.'.. I ''t JflStittt LXCt+.,"... #+cc I '.. I *)< flfl*ccfl;;i)+c++ "'"%'%+. **.ccc.s %.z,ccc* '...-..'.'.. Dp%S+c rcc ,cj. c+-.'' c: - NtsN )I pø+.'.' '*..c:_- S**p%:Lc).**-.'-.. $bøtrc* , IL.L kc+''..... '..,-.. Z Mts'-. tc..+c++cc* :"c.c+c, flsns DpI Ct.'+..,+tCc>L I. b- nct+..'.'. :. iøfl2*,.. (CCC<CK)cJ t*z..<>.j i XC,Z)cc++-'.- '. tcct4 +'.'+'%' I..'.+C<*)cTTOtD2flssSflzrI,c4. "+ +.,.. +c'r-- *ccws*c,.. &rn*,vnx>+-,... t I I I I. *<*i... I I. Iii>c>c>c.c,<z: snr c.-., c. 'c>.'<cccc.> +'..... J.+c+,+.cc*. +<,+.. Cct." :..... t. +c:n --8s$s%Ic-.,-.....' *C+,?-s CCM>(cc<tt'... I,... tc**'.%.. I Figure 3. Proton n.m.r. zeugmtogrm of the oil distribution within n intct pecn nut (Cry i1linoensis. t 8.13 MHz which ws lso used for the other experiments described below. Grdients of bout 0.1 mt cm were employed. The instrument ws Vrin DA-60 spectrometer, modified by the ddition of pulsed timeshring system. Figure 3 shows the oil distribution inside pecn nut, which contins only few per cent of wter, but gives signl bout 2 p.p.m. wide 154

7 Figure 4. Proton n.m.r. zeugmtogrrn of cherrystone clm (smll Venus mercenri) viewed edge-on. The niml ws live nd enclosed within its shell. The bright regions in the photogrphiclly processed imge represent regions of high projected wter content. The computer output hs been photogrphiclly filtered nd enhnced. 155

8 PAUL C. LAUTERBUR Figure 5. Proton n.m.r. zeugmtogrm of the thorcic cvity of live mouse. The plne of the receiver coil pssed through the lungs t right ngles to the long xis of the body, nd the imge is similr to tht which would be obtined from thick trnsverse section. from the oils in the nut met. The shell does not ffect the imge in ny wy. Similrly, the distribution of soft tissues nd fluids within clm bout 30 mm cross is shown in Figure 4. The niml ws in its closed shell, surrounded by ir. The plne between the shells lies prllel to the viewing direction. In Figure 5 prtil proton n.rn.r. zeugmtogrm of live mouse is shown. The receiver coil ws centred on the thorcic region nd ws sensitive only to tht prt of the body. The lungs my be clerly seen, but no other detil is visible (the bright spot in the centre is n rtefct. Twelve 15 s scns, recorded over 20 mm period, were used for the reconstruction, s for those in Figures 24. CONCLUSIONS Imges of objects hve hitherto been obtined by tking dvntge of their 156

9 intrinsic bility to interct with rdition, nd the resolution in such imges hs been limited by the wvelength of the rdition used. Induced interctions between mtter nd rdition, such s mgnetic resonnce phenomen dependent upon the presence of n pplied mgnetic field, my be employed to generte new kind of imge. The portion of the object within which the interction with given frequency of rdition tkes plce my be controlled by using n inhomogeneous mgnetic field, nd resolution in imges constructed from such dt is independent of the wvelength of the rdition. The qulity of the imges depends, insted, upon number of other fctors, such s the linerity of the field grdients, the uniformity of the rdition field nd the detils of imge reconstruction lgorithms or other techniques for generting imges from the dt. Reltively crude low-resolution pictures hve been generted by the use of one possible combintion of experimentl nd computtionl techniques, nd some exmples hve been shown in this pper. Higher resolution, nd pplictions to both lrger nd smller objects, seem likely to be redily ttinble s instruments nd techniques re refined. ACKNOWLEDGEMENTS Prtil support for this work ws provided by the Ntionl Institute of Mentl Helth. Grnt No. 1 R03 MU by funds from Biomedicl Sciences Support Grnt (HEW Grnt No RR 07067) wrded to the Stte University of New York t Stony Brook, nd by the Ntionl Cncer Institute. Grnt No. 1 ROl CA The grey-scle line printer progrmme ws dpted from one supplied by Professor D. Tycko nd S. Anblgn. Much of the progrmming ws done by C. S. Dulcey, Jr, nd F. W. Porretto; C. P. Weisel ssisted with computer spectrometer interfcing, nd most of the experimentl work ws done by C.-M. Li. Photogrphic processing ws crried out by Joseph A. Frnk. REFERENCES 1 P. C. Luterbur, Nture, Lond., 242, 190 (1973). 2 P. C. Luterbur, Proceedings of the First Interntionl Conference on Stble Isotopes in Chemistry, Biology nd Medicine, p 255. US Atomic Energy Commission CONF D. D. Osheroff, W. F. Gully, R. C. Richrdson nd D. M. Lee, Phys, Rev. Letters, 29,920(1972). See P. R. Smith, J. M. Peters nd R. H. T. Btes, J. Phys. A: Mth., Nuci,, Gen. 6, 361 (1973), for discussion nd review. P. Mnsfield nd P. K. Grnnell, J. Phys. C: Solid Stte Phys. 6, L422 (1973). 6 R. Gordon, R. Bender nd G. T. Hermn, J. Theor. Biol. 29,471(1970). 157