REVIEW

Annals of Nuclear Medicine Vol. 10, No. 3, 277-280, 1996

Interventional brain SPECT—A review

H.-J. BIERSACK, * E. KLEMM, * C. MENZEL, * K. REICHMANN, * W.J. SHIH** and F. GRUNWALD *

*Department of Nuclear Medicine, University of Bonn, Germany**Division of Nuclear Medicine, VA Medical Center Lexington, KY, USA

Brain SPECT with HMPAO or ECD has—due to its short accumulation period—a rather high timeresolution of approx. 60 sec. Compared to isopropyl amphetamine (I-123) and FDG-PET,shortlasting interventions may be evaluated by SPECT. Usually, a two-step approach is used,injecting one third of the dose under baseline conditions and two thirds during intervention. The firststudy is then subtracted from the second study, resulting in a "difference" image which allows tocalculate the effect of the intervention. These interventional procedures may include drug,mechanical, and mental intervention as well as ictal, blood pressure and receptor intervention.Moreover, the difference of pCO 2 after hyperventilation or hypoventilation may also be used as astimulus. The above mentioned procedures are described in detail.

BRAIN IMAGING with HMPAO or ECD has gained wide-spread clinical application in epilepsy, psychiatry andcerebrovascular diseases 1-5 as resolution could be im-proved by using dedicated SPECT systems (triple headgamma camera, annular crystal). However, the sensitivitymay be considerably improved by the application ofinterventional techniques. Pharmacological interventionincludes the injection of diamox or barbiturates (WADAtest) as well as the reduction of medication, especially inepilepsy. Mechanical intervention requires the balloonocclusion or manual compression of the carotid artery(MATAS test). This procedure may also be combinedwith the application of diamox to increase the perfusiondifference between normal and low flow areas. For theevaluation of brain function, mental intervention maybe useful. The stimuli include accoustical, visual andmotoric challenge. Above that, the speech areas maybe identified by language stimulation. The prefrontalfunctions can be stimulated using the Wisconsin CardSorting Test, especially in patients with psychiatric dis-

Based on an invited educational lecture at the 35th AnnualScientific Meeting of the Japanese Society of Nuclear Medicine,Yokohama, October 1995.

For reprint contact: H.-J. Biersack, M.D., Department ofNuclear Medicine, University of Bonn, Sigmund-Freud-StraBe25, 53127 Bonn, GERMANY.

eases. During sleep, circumscribed hypoperfusions maybe detected in sleep apnea and narcolepsy. The CO 2

-intervention allows the evaluation of the cerebrovascular(perfusion) reserve by raising pCO2 by hypoventilation aswell as hyperventilation (decreasing pCO2). The ictalintervention is the most common procedure for the proofof epileptic foci. The ictaUinterictal switch allows a local-ization of a focus in more than 90% which is extremelyuseful in patients considered candidates for temporallobectomy. Above that, D2-receptor scintigraphy usingIBZM may be performed before and after application ofD2 agonists or antagonists. This procedure allows tocalculate a basal ganglia/frontal cortex ratio which isequivalent to the binding of "cold" receptor drugs.

The here mentioned procedures will be described indetail in this review:

DRUG INTERVENTION

DiamoxAutoregulation of the cerebral blood flow (CBF) plays animportant role especially in cerebrovascular disease.' Thedegree of arterial occlusion does not correlate well withthe hemodynamic condition of the affected brain areas,as the collateral circulation is only poorly evidencedby sonography. The evaluation of the cerebrovascular

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reserve capacity in stroke patients may have a majorimpact on the management of CVD. For estimating thereserve capacity, the correlation of CBF and blood vol-ume were used. However, positioning problems lead to adegradation of the results. Since many years now, thediamox test is used for estimating the perfusion reserve.For this test, at first a baseline study using HMPAO orECD is obtained. After completion of the SPECT study,I g acetazolamide (diamox) is injected intravenously. Asecond SPECT study (split dose technique) is acquired10-20 min. after the injection of diamox. Both investiga-tions are performed with the patients head strictly immo-bilized for 1 h. Subtraction of the first from the secondSPECT data results in rCBF (stress) images duringacetazolamide-induced vasodilation, Usually, in not-com-pensated CVD, the diamox test leads to hypoperfusion inbrain areas supplied by stenotic vessels. Pavics et al.'reported on 29 patients (3 controls and 26 stroke patients)who all had transcranial Doppler sonography studies. Thesensitivity of rCBF SPECT increased from 62 to 77%after diamox provocation in stroke patients. In patientswith a reversible neurological deficit, the sensitivity in-creased from 50 to 71%. Additionally, under diamox-induced hypoperfusion of brain areas, transient crossedcerebellar diaschisis was observed.

NeurolepticsIn patients with schizophrenia or major depression, ahypoperfusion of the frontal and/or temporal lobe hasbeen reported.' The application of therapeutic drugs likehaloperidol leads to normal perfusion in these brainareas.' These findings were well correlated to the symp-toms.'

Drug reductionIn patients with epilepsy and equivocal interictal brainSPECT studies, the antiepileptic medication was reducedto provoke a focus. Six out of 10 patients with seizuresshowed a change of perfusion at the site of an epilepticfocus. 8 However, as ictal SPECT (see later) was superior,this procedure is no longer used, at least in our depart-ment. Also, the application of anexate (arteficial ictalstudy) did not yield promising results.

WADA TestBrain SPECT during WADA test was first described in1987. y For this procedure, the sodium amytal was injectedfirst. Two-5 min. later, HMPAO was given intravenouslyduring hemianesthesia of one hemisphere. The most promi-nent result was that perfusion during hemianesthesia wasmuch more pronounced in the left (dominant) hemispherethan in the subdominant hemisphere, at least in righthanded subjects. Moreover, transient crossed cerebellardiaschisis was observed. The results give rise to theassumption that the dominant hemisphere is much morevulnerable to anesthesia that the subdominant hemisphere.

MECHANICAL INTERVENTION

The MATAS test 1 ° requires the occlusion of the internalcarotid artery (left or right). It is used to predict theoutcome after permanent intraoperative occlusion of theinternal carotid artery. If no sufficient collateral circula-tion is present, hypoperfusion of the respective hemi-sphere is observed." During the last years, this procedurewas improved by preoperative temporary balloon occlu-sion of the internal carotid artery. " 2 Recent results pub-lished by Lorberboym et al.''- gave evidence that patientswith symmetric cerebral perfusion measured by HMPAOSPECT still had a high long-term complication rate fol-lowing carotid sacrifice. The scan findings in these pa-tients were not predictive of the outcome. Patients withasymmetric cerebral perfusion had alternative therapeuticapproach to carotid sacrifice and had good surgical out-come. On the contrary, our own results gave evidence thatthe MATAS test using HMPAO and the balloon occlusionwas well in agreement with the postoperative outcome."

MENTAL INTERVENTION

Acoustic, visual and motor activationAcoustic stimulation was first described in patients withschizophrenia having auditory hallucinations. 13 Studiesperformed during the hallucinogenic stimulus showedright or left sided temporal lobe hyperperfusion. Motoractivation may be achieved by asking the patient to docertain movements, especially with his finger. This leadsto circumscribed increased perfusion in the respectivecortical areas. Visual stimulation by asking the patient tolook at a complex scene or flickering light causes hyper-activation of the visual cortex. These studies were usedclinically in patients with certain diseases of the visualpathways. A baseline study may be needed to quantita-tively evaluate the activation differences. For this pur-pose, usually a split dose technique (one third of the dosefor the baseline study, two thirds of the dose for the activa-tion study) is applied. The patient is then investigated inthe same position. A subtraction image (activation minusbaseline study) allows to delineate the activated brainareas.

Language activationDespite of the importance to activate syntactic knowledgein relating words, functional imaging studies on languagemainly have focussed on processing of isolated wordsrather than sentences. 14

Former brain lesion studies suggest a different process-ing of semantic and syntactic structures. In an ethicalcommittee-approved study, 9 right handed male volun-teers (age 23 to 46 years) were investigated by highresolution SPECT using Tc-99m ECD as a tracer. 15 Thestimulus was to listen either to content words (semantic

278 H.J. Biersack, E. Klemm, C. Menzel, et al Annals of Nuclear Medicine

condition) or to short phrases containing no lexical, butonly grammatical information (syntactic condition). Fol-lowing the resting acquisition after intravenous injectionof ECD, stimulation was performed either with the se-mantic stimulus or the syntactic set binaurally over aperiod of 5'/2 minutes. The second dose was slowlyinjected during this period, thus representing the cerebralperfusion pattern during stimulation. The SPECT resultswere evaluated both semiquantitatively and visually. Quan-titative data were related to the baseline set by calculatingthe percent increase or decrease of counts per voxelnormalized to the whole brain activity in the stimulationstudy. Thus, each subject served as its own control.

Different activation patterns were observed when com-paring the two conditions. Hyperperfusion under syntac-tical stimulation (n = 4) was seen in the following areas:All 4 superior temporal gyrus (I left, 3 right), 2 inferiorfrontal gyros (1 left, 1 right) and 3 insula (2 left, 1 right).Moreover, 2 subjects had hyperperfusion within the gyruspostcentralis (1 left, I right). During semantic stimulation(n = 5), 4 subjects had hyperperfusion of the mediusfrontal gyrus (2 left, 2 right), 2 of the superior frontalgyros, the precentral gyrus and the medius temporal gyros(each 1 left, 1 both sides), 3 of the right postcentral gyrus,3 of the insula (1 left, 2 both sides), and 3 of the cuneus (1right, 2 both sides).

The results of the syntactic stimulation agree well withexperiments demonstrating disabled syntactic processingfollowing lesions of Broca's area and the insula andsuggesting the insula to be relevant in syntactic process.The semantic stimulation reflects involvement of bothhemispheres, more prominent on the right side. Thehyperperfused regions are not primary language areas.These findings are consistent with other studies using PETor SPECT which report activation outside these areas andconclude that semantic processes may be distributed overa network of brain regions. Further studies have to be doneto evaluate the handedness or sex differences. Probably,these studies may prove useful in the rehabilitation ofaphasia.

Wisconsin Card Sorting TestThe Wisconsin Card Sorting Test was applied in humanvolunteers as well as in depressed and schizophrenicpatients. This test was used to evaluate the stimulation ofprefrontal cortical areas with regard to the supposedpathophysiology of the two diseases. Studies in humanvolunteers (n = 16) showed that right or left sided activa-tion may occur. The same test was applied in a group ofdepressed (n = 26) and schizophrenic (n = 7) patients. Indepressed patients, the Wisconsin Card Sorting Test didnot show activation of prefrontal areas in 15 out of 26patients. In schizophrenics, the same was true for 2 out of7 patients. One of the clinical benefits might be to sub-

group patients with psychiatric disorders.

SleepFive patients with sleep apnea and 4 patients withnarcolepsy underwent brain SPECT using HMPAO un-der awake condition and during sleep.' 6 The most promi-nent finding was a hypoperfusion of the left temporal lobeduring sleep, whereas the right temporal lobe did not showsignificant differences. These data suggest that duringsleep the right temporal lobe remains activated.

CO2-INTERVENTION

As mentioned before, the CO 2 pressure may be used toevaluate the cerebrovascular reserve. For this purpose, thepatient may breath CO2. However, complications wereobserved using this method. We used hyperventilation inpatients with epilepsy and equivocal interictal brainSPECT. After a base-line study, the patient was asked tohyperventilate for a couple of minutes. During hyper-ventilation and low pCO 2 , HMPAO was injected intra-venously. In 4 out of 10 patients a change of thescintigraphic results was observed. It was speculated thathyperventilation leads to an increased contrast betweennormal brain tissue and a seizure focus as the focus shouldnot have autoregulation mechanisms.' However, the re-sults were discouraging with respect to ictal brain SPECTstudies.

ICTAL INTERVENTION

Overall sensitivity of interictal rCBF SPECT is 75%, with69% for low resolution systems and 84% for high resolu-tion systems." This sensitivity may be as high as 90-95%" when ictal studies are performed. For this purpose,HMPAO or ECD is injected during video and EEGmonitoring. The tracer has to be injected intravenouslypromptly after onset of the seizure, following the firstseconds after onset of the symptoms or EEG discharge.Especially in temporal lobe epilepsy, excellent resultswere obtained. Furthermore, in frontal lobe epilepsy caus-ing major clinical problems, a focus could be delineatedin more than 75%." In many cases, the comparison ofbaseline scan and ictal scan is necessary as the ictalchanges may be very distinct.

BLOOD PRESSURE INTERVENTION

In patients with a complete stroke, therapeutic strategiesare still controversially discussed. One of the therapeuticaims is an improvement of the perfusion in the strokeareas. For this purpose, the blood pressure may be el-evated to increase the perfusion pressure of the tissue. Onthe other hand, an increased risk of a rupture of bloodvessels has to be considered under high arterial bloodpressure. Here, brain SPECT may also be helpful by

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comparing the SPECT results under low and high pres-sure conditions. If the rCBF is increased duringhyperperfusion, this kind of therapy should be main-tained. However, results in a larger group of patients havenot yet been published.

RECEPTOR INTERVENTION

Since many years, brain SPECT using I-123 IBZM is usedfor imaging the striatal D2-dopamine receptors. As theblood level does not correlate with the receptor occupa-tion after application of D2-antagonists or agonists, itseems highly desirable to evaluate receptor binding inpatients under respective therapy. In a recently publishedstudy by Klemm et al., ' g 56 patients with schizophrenia,including 14 with schizoaffective disorder and one withschizophrene-form disorder, were evaluated. Fourteenpatients were neuroleptic free. SPECT was performed90-120 min. after intravenous injection of IBZM. Subse-quent semiquantitative estimation of D2-receptor bindingwas done with the use of the basal ganglia (striatum/frontal cortex) ratio. Clinical symptoms were rated with apositive and negative symptom scale and the Hamiltondepression rating scale. The striatum/frontal cortex ratiosin patients taking typical neuroleptics were significantlylower than those in the neuroleptic free subjects. Patientson atypical neuroleptics (clozapine, remoxipride) did notsignificantly differ from the neuroleptic-free patients. Foratypical antipsychotics, a dose dependent relationshipwith striatal D2-receptor binding could not be demon-strated. The ratios were not significantly correlated withclinical symptoms or with duration of the illness. Theseresults indicate that IBZM -SPECT is useful for semi-quantitative imaging of striatal D2-dopamine receptorsand for estimating their blockade by neuroleptics thusimproving drug monitoring in psychiatric patients. Fur-thermore, the findings suggest a complex relationshipbetween the antipsychotic effect of atypical neurolepticsand D2-receptor blockade.' I Similar results were ob-tained by BrOcke et al. 19

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