the neuroactivation of cognitive processes investigated with ...d. montaldi and a.r. mayes / the...

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The neuroactivation of cognitive processesinvestigated with SPECT

Daniela Montaldi∗ and Andrew R. MayesDepartment of Psychology, University of Liverpool,UK

The last ten years have seen the development and expansionof an exciting new field of neuroscientific research; function-al mapping of the human brain. Whilst many of the questionsaddressed by this area of research could be answered usingSPECT, relatively few SPECT activation studies of this kindhave been carried out. The present paper combines an evalu-ation of SPECT procedures used for neuroactivation studies,and their comparison with other imaging modalities (i.e., PETand fMRI), with a review of SPECT neuroactivation studiesthat yield information concerning normal brain function witha particular emphasis on the brain activations produced bymemory processing. The paper aims to describe and countercommon misunderstandings regarding potential limitations ofthe SPECT technique, to explain and illustrate which SPECTprocedures best fulfill the requirements of a neuroactivationstudy, and how best to obtain information about normal brainfunction (whether using normal healthy subjects or patients)and finally to highlight SPECT’s potential future role in thefunctional mapping of the human brain.

Keywords: SPECT, neuroactivation, memory, cerebral bloodflow, 99mTc HMPAO

1. Introduction

Over the past decade cognitive neuroactivation re-search has become one of the most rapidly expandingfields of neuroscience. This rapid expansion has oc-curred because technological developments have madeit possible to image indirectly the neural correlates ofcognition. Until recently the majority of neuroacti-vation studies were carried out using Positron Emis-sion Tomography (PET). However, developments with

∗Corresponding author: Daniela Montaldi, Department of Psy-chology, University of Liverpool, PO box 147, Liverpool, L69 3BX,UK. Tel.: +44 151 794 5629; Fax: +44 151 794 5635; E-mail:[email protected].

functional applications of magnetic resonance imaging(fMRI) have led to fMRI becoming the dominant func-

tional neuroimaging modality. Despite the excitement

growing within neuroactivation research, surprising-ly few SPECT neuroactivation studies have been pub-

lished. Two factors probably underlie the scarcity of

published SPECT neuroactivation studies. First, thereis a widespread belief that PET has several advantages

over SPECT as a neuroactivation technique. Second,

and probably related to this belief, there is a culturaldifference such that SPECT has primarily been fund-

ed as a tool for clinical investigation whereas PET is

more often funded as a research tool, particularly for

neuroactivation research.We shall argue in this paper that closer inspection

of the evidence indicates that these advantages are less

striking, general, or genuine than many workers be-lieve. Furthermore, there are some genuine advantages

of SPECT over PET, which are appreciated by rela-

tively few. Together these widespread misconceptionshave probably unjustifiably discouraged many from ap-

plying this imaging modality to cognitive neuroactiva-

tion research. The relative advantages and disadvan-tages of PET, SPECT, and fMRI will be discussed be-

low. We will first consider what are widely believed to

be the advantages of PET relative to SPECT as a neu-

roactivation technique. Then, we will consider whatmay be the advantages of SPECT over PET as a neu-

roactivation technique. Finally, we will briefly con-

trast fMRI and emission tomography and consider theadvantages and disadvantages of fMRI relative to the

two emission tomography techniques. Following this,

we discuss SPECT neuroactivation procedures and howthese have been used before concluding with a discus-

sion and evaluation of SPECT’s potential contribution

to this area of neuroscience.

Behavioural Neurology 12 (2000) 53–67ISSN 0953-4180 / $8.00 2000, IOS Press. All rights reserved

54 D. Montaldi and A.R. Mayes / The neuroactivation of cognitive processes investigated with SPECT

2. Comparison of PET and SPECT asneuroactivation techniques

2.1. Possible advantages of PET over SPECT

The first of the advantages that Emission Tomogra-phy studies using PET have long been considered tohave over those using SPECT is that the short half-lifeof the radiopharmaceuticals used with PET (typicallya few minutes) allows several different cognitive con-ditions to be imaged in one session. A complete ex-periment can, therefore, be easily carried out withoutsubjects needing to be repositioned. In contrast, as thehalf-life of the radiopharmaceuticals used with SPECTis generally much longer, different cognitive conditionsare best imaged on different days. This design requiresthat subjects need to attend for more than one scanningsession and the sessions must be at least 24 hours apart.It is widely believed that since the subjects must berepositioned each time, the successful use of the proce-dure is more dependent on the co-registration of scans,and hence may be liable to error resulting from incor-rect co-registration. PET as well as SPECT neuroacti-vation studies require that images acquired at differenttimes are co-registered. As PET scans are usually ac-quired over a period of around an hour, there is likely tobe considerably less positional change than will be thecase with SPECT scans that are acquired days apart sothat subjects will have moved out of and back into thescanner between scans. However, the belief that thisdifference between SPECT and PET causes a greaterproblem for SPECT is based on a misconception be-cause, as long as steps are taken to minimise excessiverepositioning variation, co-registration accuracy shouldnot depend on the extent of positional change. What isdifficult is the very fine co-registration of images anderror here arises for reasons unconnected with the ini-tial amount of separation of images. In other words,the problem can be the same for PET and SPECT.

A second advantage that PET is widely believed tohave relative to SPECT is that the nature of the radio-pharmaceuticals used with it allows a greater numberof scans to be performed with each PET experiment.This means that, relative to SPECT, PET studies cantypically compare a greater number of conditions with-in a single session and can also replicate conditionswithin a single session. However, although it is clearlyadvantageous to be able to compare more conditionswithin an experiment, it is more doubtful that beingable to replicate the same condition within a single PETsession confers any real advantage over SPECT. As

will be discussed below, the quality of the data that canbe extracted from a single SPECT scan matches thatwhich can be extracted from two or even three PETscans. This means that each condition probably has tobe run three times for PET activation studies, but onlyonce for SPECT activation studies in order to obtainsimilar quality images. So a typical PET study that has12 conditions should actually include two repetitionsof each condition, which means that only four differ-ent cognitive conditions will be included. AlthoughSPECT activation studies have until recently only in-cluded two different conditions, it has now been shownthat four condition studies can be undertaken [1]. Thereis also a potential psychological problem with repeat-ing conditions because repetition of what is nominallythe same task may well change the nature of the psy-chological processes engaged [25]. A better approachfor PET studies might be to avoid repeating conditionsunless there is a specific interest in the psychologicalchanges that may be induced (for example, see [14]),and instead compensate for the relatively poor qualityof the image data extractable from a single PET scanby including more subjects in each study.

Nearly everyone believes that PET neuroactivationstudies have a third and very clear advantage overSPECT studies: better spatial resolution. This is cer-tainly true of the optimal resolution that can be obtainedfrom most PET scanners relative to standard clinicalSPECT scanners, but there are nevertheless high qualitydedicated brain-scanning SPECT systems, the spatialresolution of which is comparable to that of less sensi-tive PET systems. A perhaps more important qualifica-tion to the widely held belief that PET has greater spa-tial resolution than SPECT relates to the analysis proce-dures that are currently run with neuroactivation data,e.g., statistical parametric mapping (SPM) [7]. Theseprocedures involve a smoothing stage that dramatical-ly reduces the spatial resolution of the image in orderto facilitate co-registration to Talaraich space [29]. Itis probably the case that the spatial resolution of theanalysed image is influenced by the analysis proceduremuch more than it is by the spatial resolution of theemission tomography system used to acquire the data(the same point applies to fMRI data).

2.2. Possible Advantages of SPECT over PET

It is less widely appreciated that SPECT techniqueswhich use long half-life radiopharmaceuticals also havesome advantages relative to PET. The first advantage isthat the technology of SPECT allows the administra-

D. Montaldi and A.R. Mayes / The neuroactivation of cognitive processes investigated with SPECT 55

tion of the radiopharmaceutical to be carried out awayfrom the scanner in a different and more comfortableenvironment in which subjects are able to perform theselected cognitive tasks under more natural conditions.Following this, the scan can be acquired up to two hourslater while the subjects rest or listen to music. Thisnot only allows for testing to be carried out in an en-vironment in which distraction can be kept at a verylow level, but crucially removes the problem of limitingsubject movement during task performance.

A second advantage of SPECT relative to PET isthe ease with which patients can be examined in neu-roactivation paradigms. This second advantage arisesout of the first one because it is easier to test patients’performance of cognitive and motor tasks in the lessconstrained and less distracting environment that canbe used in SPECT neuroactivation studies. It shouldbe noted that for exactly the same reason the ability touse an unconstrained environment also gives SPECTan advantage over fMRI in patient work.

The third advantage of SPECT is that the temporalwindow of activation to which the technique is sensitiveis around 40 seconds whereas that of PET is generallylonger. This increases the ability to detect the activatingeffects of cognitive processes that operate optimallyover short periods of time.

The fourth advantage of SPECT is that the half-life ofthe radiopharmaceuticals that can be used with SPECTallows for maximum acquisition of data for each scan.This has the important consequence that the quality ofthe data obtainable from one single SPECT scan at leastmatches that which can be obtained from two or eventhree PET scans because these have to be acquired muchmore rapidly. It is therefore possible, as discussedabove, merely to run a cognitive condition once in orderto get images of equivalent quality to those that can beobtained only with one or two repetitions if PET wereto be used.

3. Advantages and disadvantages of fMRI relativeto emission tomography

Apart from being a non-invasive imaging technique,fMRI has two other major advantages over emissiontomography. First, it offers the possibility of muchgreater spatial resolution. This possibility has, howev-er, still not been properly realized, partly because, asalready indicated, current analysis procedures such asSPM reduce spatial resolution well below the levels thatare determined by the physical constraints inherent in

the imaging method. Even so, the physical constraintsare less with fMRI and there is clearly greater potentialfor achieving higher spatial resolution with this tech-nology. One of the ways in which this potential forachieving greater spatial resolution in the localizationof activations is realised is through the accurate co-registration of functional scans to individual structuralscans. Such accurate co-registration should be easi-er to achieve within one imaging modality rather thanacross imaging modalities as is essential if emissiontomography techniques are used.

Second, fMRI acquires whole brain data very rapid-ly, thereby providing much greater temporal resolutionas well as spatial resolution. Realisation of this po-tentially greater temporal resolution in imaging brainactivations will be facilitated by the recent develop-ment of event-related recording procedures in whichthe temporal properties of the blood oxygenation lev-el dependent (BOLD) response can be related to in-dividual events or processes with precise onset times.Although the BOLD response takes several seconds toreach its peak value, it is possible to identify latencydifferences of the response under different conditionswithin one brain region very accurately. Comparisonsacross brain regions are problematic because it is cur-rently not possible to determine whether differencesare underlain primarily by variations in the timing ofneural activity or whether vascular differences betweenthe regions play a significant role. Whatever its valuefor determining the precise temporal properties of neu-ral responses eventually turns out to be, event-relatedfMRI is alone among cognitive neuroactivation proce-dures in allowing researchers to determine the patternof brain activation produced when individual and spe-cific cognitive operations are performed. The event-related procedure also allows experimenters to presenta random sequence of events of interest and so exam-ine the brain activations produced by specific cognitiveprocesses without the contaminating effects of strategicor mental set factors. This is not possible for emissiontomography procedures.

While for these reasons, fMRI has fast become theprincipal imaging technique applied to neuroactivationresearch, it is not without its disadvantages. Even morethan PET, the fMRI environment is distracting (withhigh noise levels), physically limiting (so that subjectshave to remain very still whilst performing difficultmental tasks), and can be anxiety provoking. As a re-sult, it is difficult to provide instructions and to moni-tor performance on many tasks, especially those whichwould normally require a spoken verbal output. It is,


therefore, less suitable for patient work and in somecases also for work with healthy volunteers.

Although rapid developments in technology and im-age analysis will soon overcome problems relating tofMRI data acquisition, at present this is particularlyvulnerable to artefact (motion and susceptibility arte-fact). At best, these artefacts require the application ofcorrection techniques and at worst, in some brain re-gions (medial and inferior temporal, and orbitofrontalcortices), there might be failure to detect any BOLDsignal whatsoever. Indeed, there is currently some de-bate as to whether susceptibility artefact might effec-tively “shift” an activation spatially, thus reducing fM-RI’s accuracy at spatially localising activations. It isclear, however, that despite current problems, fMRIwill dominate this field of neuroscience, although therewill remain roles for both PET and SPECT and an ac-curate understanding of the advantages, disadvantagesand potential of each emission tomography techniquewill clarify their respective and overlapping roles.

In the rest of this paper, we first outline some of thedifferent methods that have been used in SPECT neu-roactivation studies in order to identify the proceduresthat optimize the advantages of SPECT. We then se-lectively review the literature in order to illustrate howwell neuroactivation studies have succeeded in doingthis. To do this effectively it is necessary to considerhow well the design of the neuroactivation tasks en-ables one to identify the neural correlates of specif-ic cognitive processes. Although not exhaustive, thisreview includes the majority of SPECT neuroactiva-tion studies because only a few have been carried outthat focus on the identification of the neural processesthat underlie normal cognitive function. While someof the studies have involved patients, the majority ofthese have involved comparisons of patients with nor-mal controls which have yielded interesting data con-cerning the neuroactivation of normal cognitive pro-cesses. We consider studies that have examined nor-mal subjects alone, patients alone, and both patientsand normal subjects before describing the neuroactiva-tion studies that we have performed using the SME 810Novo scanner (Strichman Medical Equipment, Inc) inGlasgow. We consider that our work with this scannerexemplifies how effective SPECT can be in neuroacti-vation research.

4. Optimal and sub-optimal SPECTneuroactivation procedures

In general, the SPECT technique adopted in neuroac-tivation studies has varied in several ways: the nature

of the SPECT camera used; the radiopharamaceuticalused; the procedure (i.e., the method and time overwhich scans were acquired); and the method used toanalyse the data.

Most SPECT cameras are designed to image any partof the body rather than being dedicated to one particularregion (e.g., brain). For this reason the position of thecamera relative to the source may not always be thatwhich is optimal for maximum sensitivity and spatialresolution. Furthermore, most SPECT cameras are ei-ther single or double-headed rotating systems (i.e.,haveonly a relatively low active detector area) which mayproduce adequate sensitivity and resolution for mostclinical investigations, but would not necessarily ac-quire enough data for accurate neuroactivation studies.By contrast, dedicated brain imaging SPECT systems(such as the SME 810 Novo Tomograph, StrichmanMedical Equipment Inc.) can yield sensitivity and res-olution comparable to less sensitive PET systems. Thisis because these kinds of system are designed with mul-tiple detectors and ensure maximal proximity of thesedetectors to the source. These two factors significantlyincrease the amount of data acquired at any point intime.

Apart from any general issue such as availability,the radiopharmaceutical used should obviously be thatwhich best serves the aims of the investigation. Withrespect to neuroactivation studies, it is worth clarifyingthese aims. It was originally assumed that one impor-tant feature of the isotope is that it has a very shorthalf-life, thus allowing for multiple scanning in a singlesession comparable to most PET designs. As discussedabove, however, this feature is not crucial to the designof the study in terms of the questions it can answer sincethe accuracy of co-registration of scans acquired overtime can be reasonably independent of the initial sep-aration between scans. From a practical point of view,however, multiple scans would be beneficial as theyallow more data acquisition in a single session. Themost extensively used radiopharmaceutical for SPECTinvestigations is Technetium-99m hexamethylpropyle-neamine oxime (99mTc HMPAO) and we will argue thatthe combination of this with a high resolution SPECTsystem is the optimal set-up for SPECT neuroactivationstudies. 99mTc HMPAO is administered intravenouslythrough a forearm cannula, and reaches the brain af-ter a few seconds whereupon 5%–6% of the total dosebecomes trapped in brain tissue. 99mTc HMPAO isparticularly suited to neuroactivation studies since oncethrough the blood brain barrier, its lipophilicity changesand it is trapped such that it does not significantly redis-


tribute. Therefore, the levels of 99mTc HMPAO in thebrain tissue remain relatively constant for up to eighthours following administration. The trapping mecha-nism (unique to SPECT) of 99mTc HMPAO allows acognitive activation task to be carried out away fromthe scanner, in more natural and appropriate conditions,during which the 99mTc HMPAO dose is administered.The scan can then be carried out later, at a time onlylimited by the half-life of the nuclide (six hours) andwill produce an image of the pattern of blood flow thatoccurred in the brain at the time of injection. The longhalf-life of 99mTc HMPAO is also the source of oneof SPECT’s perceived limitations; intervals betweenscans of different cognitive conditions must be at least24 hours. Each cognitive condition, therefore, requiresits own scanning session.

Some studies have tried to overcome this perceivedlimitation by using short half-life isotopes such as133Xenon (133Xe). This radiopharmaceutical can beused for multiple scans (i.e., multiple conditions) runapproximately one hour apart (e.g., see [4]) or less.However, the relatively low spatial resolution that canbe achieved with 133Xe presents a major limitation.The resolution of 133Xe is much poorer than that ofother radiopharmaceuticals (e.g., 99mTc HMPAO) fortwo reasons. First, its short half-life reduces the possi-ble scanning time and therefore the data acquired (i.e.,reducing sensitivity) which may be increased by usingwider holed collimators but that would, in turn, reducethe spatial resolution. Second, the energy level emittedby 133Xe is lower than that of 99mTc HMPAO whichintroduces a greater scatter component within the sig-nal, further reducing resolution. It is also the casethat there is a high absorption of low energy photonsthat are emitted from the middle of the brain whichwould particularly reduce resolution of activations insubcortical structures. Since there is a trade-off be-tween brain coverage and resolution, obtaining the bestresolution achievable with 133Xe means that only a fewbrain slices can be imaged. High resolution informa-tion about the whole brain is, therefore, impossible toobtain.

Various efforts have been made to attempt to mod-el the PET design with SPECT in order to increasethe number of cognitive conditions that can be imaged.Two approaches have focused particularly on the de-sire to acquire multiple scans in a single session. First,the split-dose procedure which typically involves theadministration of two unequal doses of the radiophar-maceutical [28], although equal doses can be used. Inthis way, a proportion (e.g., 25%) of the full dose is

administered for scan one and data acquisition time isextended to compensate for the low dose. The remain-der of the dose can then be administered immediatelyfollowing the first scan, during which a different cog-nitive activity is carried out, and the subject is thenscanned again. The second approach involves dual iso-tope imaging [22] whereby two different radiopharma-ceuticals are administered in the same way as the twounequal doses in the split-dose procedure. Therefore,two scans are acquired one following the other, eachof which could potentially image the differential bloodflow patterns produced by two cognitive tasks. Whilethis approach appears promising for SPECT activationwork, its original development and evaluation [22] doesnot appear to have been applied to neuroactivation stud-ies. While both of these procedures offer some chanceof acquiring multiple scans they are perhaps limited intheir spatial resolution since, particularly with the split-dose procedure, there is considerable background noiseresidual from the first activation, and this would be suf-ficient to significantly reduce the sensitivity of the pro-cedure. Neuroactivation paradigms generally producechanges in blood flow of the order of 1%–2% and accu-rate detection of this level of change probably requiresa higher level of sensitivity than can be reliably offeredby the split-dose procedure. Although this proceduremay be less noisy when a low first scan dose is used androbust activations may be detectable using voxel-wisestatistical analysis techniques such as statistical para-metric mapping (SPM) [7], these possibilities have notyet been properly explored. It is also important to pointout that both these approaches only provide two scansper session whereas most PET designs have involvedat least four different cognitive conditions to be imagedin one, albeit long, session.

An alternative approach to this limitation has beendeveloped, evaluated and adopted by Barnes et al. [1]and Montaldi et al. [19]. This procedure does not fo-cus on multiple scans per session but on increasing thenumber of scans that can be acquired with a 99mTcHMPAO dose split equally across sessions. We foundthat reducing the dose administered for each conditionbut increasing the scan acquisition time allowed us tosuccessfully image four different cognitive conditions(each scan separated by a minimum of 24 hours). Itis important to remember that this four-condition pro-cedure can only be properly carried out with a multi-detector, section scanner rather than a rotating cameraand with radiopharmaceuticals that have long enoughhalf-lives (e.g., 99mTc HMPAO). Use of both appro-priate scanner and radiopharmaceutical is necessary to


enable data acquisition time to be extended sufficientlyto achieve the required level of sensitivity.

The requirements for the analysis of SPECT dataare similar to those for PET. For this reason neuroac-tivation data acquired from SPECT imaging has beensuccessfully analysed using SPM [18] which was orig-inally developed for PET analysis [7]. While SPECTdata can be analysed using SPM it can also be analysedusing a regions of interest approach (ROI). Indeed, it isprobably the case that due to the richer data acquiredwith SPECT’s longer acquisition time, SPECT is moresuitable to this form of analysis than is PET. Accuracywith either technique (SPM or ROI), however, requiresmaximal sensitivity and resolution and both techniqueshave advantages and disadvantages (for a discussionsee [18]).

5. SPECT activation studies of cognitive function

5.1. SPECT neuroactivation studies with normalsubjects alone

One of the few examples of work focused on normalsubjects has been provided by Goldenberg and his col-leagues (for example [9]). These workers used 99mTcHMPAO mainly to explore visual imagery processes.In an initial study [8], they compared the activationsproduced by resting, encoding meaningless “words”,encoding concrete words, or encoding abstract words.With the concrete words, subjects were either instruct-ed to encode in the way they chose spontaneously orto use visual imagery. Relative to the three other con-ditions, encoding concrete words activated the inferiortemporal and occipital regions bilaterally.

In subsequent work, Goldenberg and his col-leagues [9] used two different comparisons to identifythe activating effects of using visual imagery. First,they compared activations produced by judging the cor-rectness of high and low imagery sentences, and sec-ond, they compared counting the corners of letters withrehearsing the alphabet. The second comparison wasnot successful in isolating meaningful activational ef-fects, but it was found that subjects who reported morevivid imagery in the corner counting condition showedmore activation in inferior temporal and occipital re-gions. Importantly, these regions were also activatedmore when judging the correctness of concrete relativeto abstract sentences. The results found by this groupin later experiments did not, however, agree in all re-spects with these earlier findings. Thus, Goldenberg

et al. [11] found that although judging the correctnessof high imagery sentences relative to low imagery sen-tences produced more inferior occipital activation, itproduced less inferior temporal activation.

Several points about this particular study are worthnoting. First, it was done very early, well before func-tional imaging with PET had become an establishedprocedure with normal subjects. Second, for this rea-son, it used a ROI approach in which the regions weredrawn using a template rather than individual MRIscans. As with most ROI approaches, the regions didnot cover the whole brain so the method could not beexploratory and hence had to depend on having rea-sonably well supported hypotheses about which brainregions are likely to be activated by using visual im-agery. Third, and relatedly, most of their studies in-volved an analysis which depended on inter-subjectcomparisons rather than the intra-subject comparisonsthat were shortly to become standard in most neu-roimaging studies. The advantage of intra- relative tointer-subject comparisons is, of course, that biologicalvariability across subjects is removed as a source ofnoise in the analysis.

We can also use Goldenberg and his colleagues’s se-ries of studies to illustrate several further points. First,the lack of consistency across their studies indicatesthat replication in neuroimaging work is of critical im-portance, particularly when the underlying hypothesesare only weakly supported. In our view, insufficient at-tention has typically been given to replication in func-tional neuroimaging research.

Second, the work nicely illustrates the strategy ofusing several tasks in order to isolate specific cogni-tive processes. It is highly unlikely that one subtrac-tion can successfully separate a key process from otherprocesses that often work in conjunction with it, butthe use of several comparisons between different tasksstands much more chance of doing so. Only when allcomparisons either activate the same regions, or excep-tions can be convincingly explained, can one be con-fident that the activating effects of a specific processhave definitely been isolated. It is worth noting herethat SPM provides a specific conjunction analysis thatallows pairs of tasks to be analysed in a combined fash-ion such that only those brain regions involved in thatsingle process, common to all subtracted pairs, will beactivated significantly.

Third, imagining colours and maps produced similaractivations to each other when SPECT was used as theimaging modality [10] whereas when steady state elec-trophysilogical potentials (“DC shifts”) were record-


ed from the scalp negative shifts were maximal overparietal sites when subjects imagined maps, but weremaximal over temporal and occipital sites when sub-jects imagined colours [30]. This probably means thatthe SPECT procedure used by Goldenberg and his col-leagues was a fairly insensitive and blunt instrument.Part of the reason for this may be that the SPECT studyinvolved inter-subject analyses while the DC shift studyinvolved intra-subject analyses. This may partially ac-count for the increased sensitivity of the latter techniquewhile illustrating the limitations of the inter-subject de-sign. Nevertheless, it is likely that blood flow measuresare correlates of neural processes that overlap with,but are not identical with those that correlate with DCshifts, so the two imaging modalities may be sensitiveto slightly different neural processes. If so, this couldbe exploited in future imaging research.

5.2. SPECT neuroactivation studies with patientsalone

An example of a neuroactivation experiment usingSPECT to investigate cognitive function in a patientwith an interesting form of neurological damage was astudy performed by Cardebat et al. [4] using 133Xe. Thedata were analysed using an ROI procedure in whichthe ROIs were drawn directly onto the SPECT images.Their patient had semantic dementia characterized by acategory-specific deficit in semantic knowledge of an-imals (the patient’s knowledge of objects was relative-ly preserved). When she successfully processed thesemantic features of object names, the patient showedactivation in the left posterior and middle temporal cor-tex. The authors interpreted this activation as encom-passing Wernicke’s area and argued that it reflected theachievement of a match between auditory-lexical in-put and semantic knowledge for items with the kindsof multimodal representations that man-made objectshave. As expected the patient failed to process the se-mantic features of animal names successfully and, pre-sumably for this reason did not activate the temporalcortex regions that she activated when she managedto retrieve the semantic features of man-made objects.Instead, her left and right inferior frontal regions wereactivated. The authors viewed these regions as corre-sponding to Broca’s area and its mirror image in theright hemisphere, and interpreted their activation as re-flecting a failed phonological strategy to evoke the vi-sual semantic features which they argue are charactisticof animals.

This study has several serious limitations. First, al-though SPECT with 133Xe enables several scans to becompleted within a few hours, due to the propertiesof the 133Xe isotope, the technique has considerablylower spatial resolution than does SPECT with 99mTcHMPAO. This means that the general accuracy of thestudy was very limited.

Second, partly for this reason, blood flow was onlymeasured in a single slice so it was impossible to ex-plore activations except in a very small brain volumealthough the authors did ensure that the analyzed slicecontained only intact neural tissue.

Third, the ROI analysis procedure was anatomicallyinaccurate because it failed to co-register the SPECTimages with individual structural MRIs in order to iden-tify the ROIs as precisely as possible. Moreover, theSPECT images on which the ROIs were drawn wouldthemselves have been of particularly low resolution;this would have reduced further the accuracy of the ROIdefinition.

Fourth, the psychological design of this study meantthat there was no chance of discovering whether re-trieving semantic information about man-made objectsactivates different brain regions from those activated byretrieving semantic information about animals. Thisis because the patient failed to retrieve animate infor-mation. It is generally recognized that to image theactivating effects of a process it is wise to get a subjectto perform that process! The patient was, in fact, alsoclearly impaired in her semantic knowledge of man-made object names so the ability to image the retrievalof this kind of knowledge must also have been verylimited. It would have been much more useful to haveimaged normal subjects who have no problem retriev-ing both animate and inanimate semantic informationin order to see how the activations shown by the patientdiffer. If this had been done, it is possible that the au-thors might have found more frontal activations in bothconditions in their patient because she would have beentrying much harder than normal people to retrieve notonly animate information, but also inanimate informa-tion. This seems likely given that frontal activationsare believed to reflect the organizational processes thatare involved when cognitive activity is not automatic.

This last limitation relates to a general issue aboutwhether there are some aims which can only be ful-filled by doing neuroactivation research with patientsrather than people with intact brains. There are at leastthree aims which are certainly best addressed by usingpatients. First, by imaging patients with appropriatelydesigned studies it is possible to determine whether or


not there has been re-organization of the brain. Thiscan be achieved by identifying whether or not new brainstructures have taken over the mediation of cognitiveprocesses at which a patient is still performing nor-mally or surprisingly well despite damage to structureswhich mediate the key process(es) in normal people.Clearly, this is only possible to do by investigating braindamaged patients in whom re-organization of cognitiveprocesses may have occurred. Also, the aim can onlybe achieved when patients are performing the imagedcognitive processes well or even completely normally.

Second, imaging of patients also enables one to ex-plore the causal role played by specific brain structuresin producing activations in connected brain regions.For example, if the amygdala modulates the activityof extrastriate neocortical visual regions to emotionallysignificant visual stimuli via a backprojection mech-anism, then patients with selective amygdala damageshould not show the appropriate kind of extrastriatemodulation to emotionally significant visual stimuli incomparison to neutral visual stimuli. This kind of aimcan obviously not be achieved by studies of normalpeople with intact brains.

Third, patients are also critical for exploring whetherspecific activations are essential for the successful com-pletion of a particular cognitive function. For example,neuroactivation studies have often found that retrievalof memories activates the precuneus. It could be, how-ever, that such activations play no role in the process ofretrieval, but rather reflect processes that are inciden-tally triggered when memories are retrieved althoughthese processes play no role in retrieval. Whether or nota region must be activated in order for a function to becompleted successfully can obviously be best achievedby imaging patients with the appropriate selective braindamage. If the damage disrupts the function whichactivates the critical structure in normal subjects, thenthe activation is probably critical to the function, andthis can be determined without imaging. However, ifthe damage does not disrupt the function, one cannotbe confident that this proves the activation is incidentalto the successful completion of the function becausere-organization may have occurred following the braindamage. In order to show that this has not occurred,one needs to show that the patient displays activationsin the same structures as normal people when perform-ing the function in question apart from also showingno activation in the damaged region bearing in mindthat, in many cases, even high quality structural MRIinformation cannot necessarily completely discount aregion’s ability to function.

It should be noted,however, that all three of the aboveaims, that are critically dependent on using patients,can only be achieved if the activations shown by thepatients are compared with the activations produced byusing the same cognitive comparisons in normal sub-jects. This is clearly relevant to the study of Cardebatet al. [4], which is hard to interpret because it makesno comparison with the activations that normal peopleshow relative to a resting baseline when retrieving se-mantic information under the same conditions as thepatient. A similar comment applies to a study of Carde-bat et al. [5] which used 133Xe SPECT in an activationstudy of language processing in a patient with deepdysphasia. Although this patient showed more rightmiddle temporal cortex activation in a semantic wordmonitoring condition relative to a condition involvingpassive listening to a foreign language, the authors’ in-terpretation that the patient had shown a compensatoryre-organization in which the right hemisphere had takenover concrete word processing can be questioned. Theinterpretation would have been far stronger if, using thesame activation paradigm, it had been shown that thissame comparison consistently activates left hemispherestructures in normal people. Even if one wants to plotchanges in the brain activation produced by a specificprocess over time in patients with deteriorating condi-tions such as dementia or in whom there may be a pos-itive response to drug or other treatments, the interpre-tation of results should be far easier if it is known whatactivations this process produces in normal people.

5.3. SPECT neuroactivation studies with patients andnormal subjects

Even when SPECT neuroactivation studies with pa-tients have also included normal subjects as a compar-ison group, they have not typically attempted to ensurethat patients perform as well as their control subjectson the “active” task. This is well illustrated by compar-isons between a baseline state and performance on theWisconsin Card Sorting Test (WCST) in schizophren-ics and normal subjects. Schizophrenics are known tobe impaired at this task so it is not surprising that, un-like their normal control subjects, schizophrenics usu-ally fail to show greater frontal activation when tryingto perform the WCST (for example, see [6,23]).

Activations produced by memory processing havealso been examined in studies using patients and con-trol subjects. An example of such a study is providedby Busatto et al. [3]. These workers used 99mTc HM-PAO in a split-dose design (described above). They ex-


amined the activating effects of recalling the responseword of a series of learnt word pairs in medicatedschizophrenic patients and a group of age, sex, andhandedness matched normal control subjects. The ac-tivation produced by this retrieval condition was com-pared with the activation produced by a baseline con-dition in which subjects were presented 40 word pairsaurally twice in succession with the instruction of pay-ing attention to the association between the words andrepeating the response word. The imaging results wereanalysed using a region of interest (ROI) approachwhich included regions in the medial temporal lobes,the cerebellum, the thalamus, and a variety of neocorti-cal sites such as parts of frontal, parietal, and temporalcortex. Relative to the baseline condition, retrieval inthe normal subjects produced more activation not onlyin the left medial temporal lobes (MTL), but also inthe left inferior frontal and anterior cingulate corticesas well as in the right cerebellum. This may have beenthe first functional neuroimaging study to demonstratesuccessfully that retrieving verbal materials activatesthe left MTL region as would be expected on the basisof lesion studies of this region.

One of the main aims of the study was to determinewhether the schizophrenics would show reduced MTLactivation relative to their normal control subjects whentrying to recall the response words of word pairs towhich they had been exposed earlier. The rationale forthis was the observation that schizophrenics typicallyperform poorly on memory tasks, which are known todepend in part on functional activity in the MTL re-gion. Surprisingly, the levels of activation the patientsshowed not only in the MTL ROI, but also in the frontallobe ROIs did not differ from those of their control sub-jects. This is surprising not only because independentevidence suggests that the MTLs are malfunctional inschizophrenics, but also because the patients’ memoryperformance was significantly worse than that of theircontrol subjects.

This study represents a good example of the effectiveexploitation of the advantages of SPECT in neuroac-tivation studies except that the ROI procedure did notco-register SPECT images with corresponding struc-tural MRIs so as to help identify the ROIs accurately.However, two findings of this pioneering study war-rant comment about its design from a cognitive pointof view. The two findings were that, first, the MTLactivation was seen in both subject groups and second,this activation was not reduced in the schizophrenicsdespite their worse recall.

The first finding is puzzling because the baselinecondition used seems to have involved the encoding of

the word pairs for which recall was later tested in theother condition. In other words, recall was found toproduce more MTL activation than encoding. But thisis against the main run of results that has been foundwith PET studies of memory. These studies usuallyfind that encoding produces more MTL activation thanretrieval (see [15]). Although instructions to remem-ber the word pairs were not given during the encod-ing baseline scanning condition, this should not havemattered because what is encoded determines subse-quent memory and subjects should have been attend-ing to and encoding the associative links between thewords. Busatto et al. clearly intended that the retrievalcondition involved all the processes present during thebaseline condition and also the retrieval processes thatshould have been specific to it. However, it has beenargued that encoding more novel materials producesmore MTL activation than does encoding familiar ma-terials and the words were more novel during the en-coding condition (see [15] for a review). The balanceof the neuroactivation literature would, therefore, leadone to expect that, if anything, the baseline conditionshould have produced more MTL activation than theretrieval condition.

The second finding is also puzzling because if re-trieving verbal memories activates the MTL, then onewould expect that activation should increase in pro-portion to the rate at which memories are being re-trieved. But this rate was reduced in the schizophrenicpatients relative to their control subjects. Schacter andhis colleagues [26] have found support for this viewthat MTL activation increases as retrieval success in-creases in a study which varied the level of retrievalsuccess in normal subjects. The subjects who retrievedmore successfully showed significantly more MTL ac-tivation. Nevertheless, a study by Petersson et al. [24]suggests that retrieval of overlearnt materials may acti-vate the MTL less under some circumstances than theretrieval of less well learnt materials. Therefore, bothrate of successful retrieval and the difficulty of produc-ing such retrieval may sometimes increase MTL acti-vation. It seems likely, however, that, in the Peterssonet al. study, the extent of difference in retrieval successbetween the two retrieval conditions was far lower thanin the Schacter et al. study. Therefore, there may bea complex function linking retrieval success and effortto level of MTL activation, the nature of which is stillunknown.

The main findings of the Busatto et al. study are,nevertheless, to some extent in conflict with the litera-ture. They may be correct, but clearly should be repli-


cated before they can be accepted with confidence. It isalso worth noting that the comparison with the encod-ing baseline is very hard to interpret. There is evidencethat encoding which leads to better subsequent mem-ory causes more MTL activation than does less suc-cessful encoding (see [2,15,31] for a review). As theschizophrenics’ encoding led to less successful retrievalthan the control subjects’ encoding, one would expectthat this condition would give rise to less MTL acti-vation in the patients. This would need to be checkedby using a baseline that activates the MTL less and toan equivalent extent in the two subject groups or byusing a different baseline condition such as retrieval ofsemantic verbal associates. In addition, confidence inthe reality of the two main findings would be increasedif (a) the two scans were completed days apart so thelevels of 99mTc HMPAO would have returned close tobaseline levels, and (b) the ROI analysis was comparedwith a more standard technique such as SPM in orderto determine whether both techniques yielded similaractivations.

5.4. SPECT memory neuroactivation studiesconducted with the Glasgow brain-dedicatedscanner

In the only study that examined the activating effectsof retrieval [17] we attempted to achieve the first ofthese aims and use a more appropriate baseline in astudy which compared the activations shown by am-nesic patients and normal subjects when they recalledthe response word of previously learnt word pairs. Theactivations produced by this kind of verbal episodicretrieval were compared with the activations producedby retrieving the verbal semantic associates of similarstimulus words. This is a more appropriate baselinecomparison condition because recalling overlearnt se-mantic associates is not disrupted by MTL damage orany of the lesions that cause amnesia. In other words,semantic retrieval of this kind should produce minimalMTL activation. The comparison is not perfect, how-ever, because all retrieval is also associated with en-coding of information into memory (people can subse-quently remember what they recalled during scanning).There were 12 normal subjects in the study: six of theselearnt the word pairs to a high level whereas the othersix received much less training. In the episodic recallcondition, subjects were shown the first word of eachpair that they had studied and asked to try and recallthe word that had gone with it during the study session.In the semantic recall baseline condition, subjects were

shown similar concrete words one at a time and askedto produce another word that was semantically linkedto the presented word. The two conditions were run ina counterbalanced order several days apart.

The aim was to compare the episodic retrieval acti-vations in a group of subjects with high levels of recallsuccess and a group of subjects with a low level of re-call success. It was also intended that the recall of theless successful group of control subjects would matchthat of the amnesic patients, who received levels oftraining equivalent to that of the high performing groupof control subjects. If the patients showed a differentpattern of activation from the low performing normalsubjects, this would be evidence that their brains hadre-organized. Only if their recall was similar to that oftheir control subjects could such an inference be drawn.In the same way that the motor activations of a para-lyzed person will obviously be abnormal, one wouldexpect the memory activations of someone who cannotremember to be very abnormal.

In this and our subsequent SPECT neuroactivationstudies, a head dedicated system with high spatial res-olution was used and the data obtained were alwaysanalysed using SPM. The results revealed an interest-ing double dissociation which is very similar to the onereported by Schacter et al. [26]. We found that the nor-mal subjects with good verbal recall showed significantleft MTL activation that was greater than that foundin the normal subjects with poor verbal recall. Theselatter subjects did not show significant MTL activation,but they did show significant frontal lobe activation bi-laterally that was greater than that found in the normalsubjects with good verbal recall. The good recall sub-jects did not show significant frontal lobe activations.These results strongly suggest that MTL retrieval ac-tivations reflect the number of episodic memories thatare reactivated in a given period of time whereas acti-vations in at least some frontal lobe regions reflects thedegree to which effortful and intentional organizationalretrieval search and checking processes have been acti-vated. Such processes would have been activated morein the subjects performing poorly whereas the subjectswith very good recall could have relied mainly on au-tomatic retrieval processes that minimally involve thefrontal lobes.

The results of the amnesic group remain to be ful-ly analysed with SPM, but we have done a prelimi-nary ROI analysis with individual co-registered MRIscans [16]. This indicates that the activation patternshown by the patients was not completely identical tothat shown by the control subjects who showed equiv-


alently low retrieval success. The patients showed agreater left lateral frontal cortex activation than theirretrieval matched control subjects. This suggests thatthe patients’ neural processing of retrieval may haveundergone some re-organization. However, it is al-so possible that, they may have adopted a differentstrategy for achieving retrieval because of their long-term experience of having poor memory. This strategicadaptation may have exploited the planning capacityof parts of the left frontal cortex. The possibility isconsistent with a meta-analysis of imaging studies ofretrieval [21], which concluded that the left pre-frontalcortex is particularly activated when executive process-es are required to achieve successful retrieval.

In two other studies, we examined the activationsproduced by encoding information into memory. Ourfirst study [18] extrapolated from a study of Grady etal. [12] in which the activations produced by trying toremember new faces was compared with the activationproduced by judging which of two lower face picturesmatched an upper picture. Both studies examined theactivations produced by normal subjects. Unlike Gradyand her colleagues, we examined memory for novelcomplex scenes, and also unlike their study, we in-structed subjects to encode the pictures in the active en-coding condition in a meaningful and associative fash-ion in which they tried to identify the links between theobjects in different parts of each picture. The low levelperceptual matching baseline condition was supposedto place similar perceptual processing demands on thesubjects, but to discourage meaningful associative en-coding. Ten normal control subjects performed boththese conditions in a counterbalanced order with sev-eral days between the performance of each condition.We examined memory of the subjects for the picturesshown in both conditions in two ways. First, subjectswere asked to recall as much as the could from a limited,self-selected subset of the pictures, a kind of retrievalthat taps the ability to remember associations betweenobjects shown in individual studied pictures. Recallwas close to floor for pictures shown in the perceptualmatching condition, but good for pictures shown in theencoding condition. Second, the subjects were givena recognition test for the pictures shown. Recognitionwas very good and did not differ for pictures shown inthe encoding and perceptual matching conditions.

One of the main aims of the study was to determinewhether encoding associative features of complex pic-tures into memory produced MTL activation. In orderto do this it was necessary to try and match the levelof item (picture) memory shown by the subjects be-

tween the encoding and matching conditions, and getbetter associative memory from the encoding condi-tion. The recognition test tapped item memory, whichwas matched between the conditions, whereas the re-call test tapped associative memory, which was betterin the encoding condition. There is a widely held view,based on lesion studies (see [15] for a review) that theMTL is critical for both item memory and memory forassociations between items. Although it should, there-fore, activate when either items or associations betweenitems are encoded into memory, to show that encod-ing associations into memory specifically activates theMTL it is necessary to match memory for items acrosscompared conditions so that only associative memorydiffers. We had, therefore, succeeded in doing this.An SPM analysis showed that the encoding conditionproduced more activation than the perceptual matchingcondition in the left anterior MTL (Fig. 1(a)) and leftanterior cingulate cortex as well as in the right frontalcortex. The same pattern of activations was also foundwhen an ROI method of analysis was used. The ROIanalysis did, however, find that there was also a weakright MTL activation so although the results of the twomethods of analysis were closely matched, they did notproduce identical patterns of results.

The results of this study have several implications.First, they show that the activations produced by en-coding pictures into memory found with SPECT arebroadly similar to those which have been found withPET [12]. This shows that the appropriate SPECT sys-tem may be as sensitive as PET at detecting the rela-tively small blood flow changes triggered by cognitiveprocesses. The same conclusion can be drawn from theretrieval activation study.

Second, our results provide support for the view thatMTL encoding activations are typically anterior whendetected by emission tomography as has been argued onthe basis of a meta-analysis by Lepage et al. [13]. Whenwe repeated this study using fMRI [20] we found thatthe MTL activations detected were also left-sided, butthey were in the posterior MTL. Such posterior MTLactivations have typically been found when the imagingmodality has been fMRI rather than emission tomog-raphy (see [27]). Our results also provide strong sup-port for the view that this apparent difference betweenemission tomography and fMRI may not always relateto differences in the encoding paradigms that have beenused with these two imaging modalities, but may relateinstead to susceptibility artefact reducing the signal tonoise ratio of the BOLD response in the anterior MTL.The lesion literature gives no strong reason for expect-


ing MTL encoding activations to be either anterior orposterior so it may be that the MTL is activated alongits entire length, but slightly more strongly in the an-terior portion so that more posterior activations are notalways detected by emission tomography. This patternwould be reversed with fMRI because susceptibilityartefact reduces signal strength at the anterior end ofthe MTL.

Third, our results also indicate that broadly similarresults are found with different methods of analysissuch as SPM and ROI. Although cross-validation isnot the same as validation, it is essential that differentmethods of analysis with equivalent face validity shouldgive broadly the same results otherwise the data wouldbe uninterpretable. Where the methods give differentresults further evidence needs to be sought in order toconfirm which result is correct. For example, only theROI method found that picture associative encodingproduced right MTL activation. Although such right-sided activation might well be expected to be producedby the encoding of complex visual materials such asscenes, it could be that closely equivalent levels ofright MTL are produced in the perceptual matchingcondition so that the activations cancel each other outwith some forms of analysis (see [18] for a more in-depth discussion of this).

Some more light was thrown on this issue in a secondpicture encoding activation study that we performedwith normal subjects using the same SPECT systemand the SPM method of analysis. In this study, we madea number of modifications to what we had done be-fore. First, by halving the dose level of 99mTc HMPAOfor each scan, while extending acquisition time [1],we were able to run the first four condition SPECTneuroactivation study with normal subjects. As PETrequires repetition of conditions to achieve the sameimage quality, this effectively enabled us to image thesame number of different cognitive conditions as PET.Second, we modified the encoding condition so thatsubjects now saw a series of sets of three different pic-tures. For each set, they had six seconds to decidewhich of the lower two pictures was thematically mostsimilar to the single upper picture. As they also had sixseconds to make their perceptual decision in the per-ceptual matching condition and there were also threesimilarly arranged pictures, the two conditions werevery alike except with respect to how subjects encod-ed the pictures. Third, four conditions were neededbecause in two of them subjects either made themat-ic judgements or perceptual judgements about pictureswith which they were already familiar. In the other two

conditions, they made these two kinds of judgementabout pictures which they had not seen before. Fourth,associative memory for objects in the pictures was thistime assessed by a recognition test rather than a recalltest. We also debriefed subjects in order to determinewhether or not they had noticed at the time of encodingwhether the pictures were novel or familiar.

Apart from replicating the finding of the first studythat associative encoding activates the left MTL, thissecond encoding study had two further aims. First, itaimed to determine whether associative encoding al-so activates the right MTL when the data are analysedwith SPM. Second and more important, it aimed to de-termine whether novelty detection activates the MTLeven when a strenuous attempt is made to match en-coding between novel and familiar pictures by givingvery specific encoding instructions. It has been ar-gued that the detection of novelty leads to MTL acti-vation, but it remains unclear whether any such effectis caused by novelty detection per se, the attentionalorienting that such detection typically produces, or theadditional encoding that such detection may producewhen encoding is spontaneous (see [15] for a reviewof these issues). We aimed to minimize differences inencoding between novel and familiar pictures. Also,the demanding nature of the encoding in which subjectswould have to engage made it seem likely that atten-tional orienting to novelty would also be minimized.Finally, we wanted to determine whether encoding fa-miliar pictures would activate the MTL as much as en-coding novel pictures. This aim relates to the questionof whether encoding into memory activates the MTLregardless of whether subjects perceive the informationbeing encoded as novel or familiar.

The results were clearcut, but surprising. First, on-ly thematic encoding gave rise to significant associa-tive recognition for the contents of the pictures and thisencoding produced more left MTL activation than theperceptual matching condition regardless of whetherthe pictures were novel or familiar (Fig. 1(b)). Interest-ingly, the activation was relatively posterior althoughwe do not believe that a different part of the MTL wasactivated in this second study than in the first. Rather,it is likely that activation strengths differed between thestudies in anterior and posterior regions of the MTL.Second, when encoding was balanced across compar-isons, there was no evidence that novelty of the pictureswas associated with significant activation anywhere inthe brain, let alone in the MTL. No activation occurreddespite the fact that subjects claimed to have detectedwhether pictures were novel or familiar during the the-


Fig. 1. SPM z-maps of left MTL activations produced by encoding processes carried out during (a) the associative encoding task (−16 −10 −16,BA 28/35) and (b) the thematic encoding task (−14 −36 0, BA 27/30) when compared to the same baseline perceptual task.

matic encoding and perceptual matching sessions. Sothe results indicate that novelty detection alone does notproduce significant MTL activation. Third, encodingthe familiar pictures thematically not only produced asmuch left MTL activation as did encoding novel pic-tures, it also produced a right MTL activation. This in-dicates that when encoding is to some extent controlledand associative memory is effectively produced, the fa-miliarity of pictures does not reduce the role played bythe MTL. The greater activation that encoding familiarpictures produced may have occurred because the the-matic encoding could be carried out more effectively onslightly familiar relative to completely novel pictures.

Thematic encoding was also found to activate theprecuneus bilaterally and the inferior parietal cortex onthe left and the extent of these activations correlatedstrongly with the amount of associative recognition thatsubjects showed for the pictures. These findings illus-trate the importance of using a convergent operationsapproach which combines lesion with functional neu-roimaging research. This is because these activationsraise two questions. First, are these activations crit-ical for successful associative recognition of the pic-tures? As already indicated, one way of answering thisquestion is to find out whether patients with relativelyselective damage to the activated structures show im-paired associative recognition. Second, what process-es do these structures mediate? Again, this questioncan be addressed by detailed analysis of the cognitivedeficits shown by patients who have relatively selectivedamage to the structures that showed activations duringthe thematic encoding of the pictures.

The Glasgow series of SPECT neuroactivation stud-ies has used a SPECT system with good sensitivity andspatial resolution. None of the other studies describedabove used this optimal system. The Glasgow seriesalso used 99mTc HMPAO whereas some of the otherstudies used radiopharmaceuticals such as 133Xe thatfail to exploit maximally the potential advantages of

SPECT. Further, whereas the procedure adopted in theGlasgow series involved up to four intra-subject scanconditions, each separated by at least 24 hours, manyof the other studies discussed above used noisier pro-cedures (e.g., inter-subject comparisons or split dosetechnique) which would have led to reductions in signalsensitivity and spatial resolution. Finally, the Glasgowseries used both SPM and MRI-based ROI analyseswhereas some of the other studies used less standard-ized and less structurally accurate analysis procedures.

6. The future of SPECT neuroactivation research

The previous section illustrates that SPECT may beas effective as PET when used appropriately in cog-nitive neuroactivation studies although this capabilityhas rarely been exploited. Equivalent effectiveness willinvolve the ability to use a SPECT system with highspatial resolution and the ability to image four cogni-tive conditions. Indeed, in the near future, SPECT sys-tems with spatial resolution of 5 mm will be available,and 3.5 mm resolution systems are on the horizon (seewww.neurophysics.com). In other words, SPECT res-olution in the future will be even more closely compa-rable to that of PET. It seems very likely, however, thatwithin a few years the modality of choice for nearly allcognitive neuroactivation studies will be fMRI and notemission tomography. Even so, for some time to come,there will be a need to cross-validate fMRI and emis-sion tomography effects. SPECT should play an im-portant role in such cross-validation procedures. Fur-thermore, there are several specific areas where the useof SPECT in neuroactivation studies is likely to haveadvantages not only over PET, but also over fMRI.

First, SPECT is very good for imaging patients whoare not well oriented and who, therefore, are likely tobe become confused in the constraining atmosphere re-quired for fMRI and even PET. This is because sub-


jects can perform the various challenge tasks in a freeenvironment where the radiopharmaceutical can be ad-ministered to them. The unique value in using patientsin neuroactivation research has already been discussed.In that earlier discussion, the importance of using nor-mal control subjects as a baseline comparison for thepatients was indicated. One of the main aims of usingpatients is to examine whether re-organization of brainprocesses has occurred. Future work may develop stan-dardized paradigms, which should mean that it will beunnecessary to use normal subjects repeatedly, but pa-tients’ activations will be possible to compare with astandardized normal data base.

Second, for the same reason, SPECT will be the on-ly possible imaging modality in which the activatingeffects of large scale movements can be examined overa period of about one minute. For example, one couldexamine the activating effects of planned intentionalmovements through a complex spatial environment rel-ative to the activating effects of being passively movedthrough a similar environment. In the foreseeable fu-ture, only SPECT will have this capability.

Third, SPECT is the best imaging modality for lo-calizing which brain structures are being disrupted bytranscranial magnetic stimulation (TMS). This tech-nique is of great interest because it offers a method fortemporarily disrupting electrical activity in the cere-bral cortex in a relatively focal way and with minimaldiscomfort to subjects. TMS can be viewed as a re-versible lesioning technique in which it is possible toknow within a few milliseconds when the disruptionoccurred. This means that the technique can be usedfor determining whether a specific neocortical regionplays a critical role in a cognitive function. Not on-ly can it be used for this purpose, but it can even beused for determining when a structure becomes criti-cally involved in mediating a cognitive function. How-ever, there is major problem with TMS. The electricaldisruption that it produces is not particularly focal andits localization is hard to determine as it depends onfactors such as the orientation of fibre tracts near thecortical surface. Localization may even be influencedby the basal activity of the tissues being stimulated.Ideally, one should use an imaging modality to localizechanges in neural activity whilst subjects are engagedin the processes that TMS disrupts. Activity can then becompared whilst doing this task both in the presence ofTMS and without it in order to determine exactly whatthe effect of the stimulation is. Applying the magneticcoils to the same position on the head is far easier todo in an unconstrained environment which is availablewith SPECT, but not with PET and fMRI.

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