J Neurol (2003) 250 [Suppl 1]: I/15–I/23DOI 10.1007/s00415-003-1103-1

Andres O. Ceballos-Baumann Functional imaging in Parkinson’s disease:activation studies with PET, fMRI and SPECT

Introduction

Activation studies provide a means of studying regionalcerebral function in man in vivo under both resting andactivating conditions. Most activation studies publishedso far relied on the use of H2

15O PET measurements ofregional cerebral blood flow (rCBF) as index of synapticactivity. The functional resolution of state of the art PETcameras is 48 mm. This is adequate to enable blood flowand metabolic changes in the lentiform nucleus andhead of caudate to be separately monitored in group av-eraged studies but does not allow putamen, pallidum,and subthalamic function to be accurately differenti-ated.

fMRI, in comparison to PET, is characterized byhigher spatial and temporal resolution, better availabil-ity and the absence of radiating isotopes. Measurementof blood oxygen level dependent (BOLD) signal in-creases with functional fMRI offers the opportunity toanalyze the functional networks in PD and its pharma-cological modulation with high spatial and temporalresolution in comparison to PET. In contrast to PET,

with averages movement related cortical activation overlong time periods of up to 1.5 minutes, event-relatedfMRI offers the advantage to investigate BOLD signal in-creases related to single movements and avoids theproblem of long acquisition times which may confounddata with processes not related to movement. Event-re-lated fMRI may therefore reflect more precisely move-ment-related cerebral activity.The use of fMRI,however,is limited in patients with implanted electrical devices.PET in deep brain stimulation is particularly attractiveto study the models of basal ganglia thalamocorticalloops. The effects of discrete perturbations at differenttarget structures throughout the basal ganglia-thalamo-cortical circuitries can be studied with implanted im-pulse generators. Patients can undergo repetitive scansunder different stimulation conditions in one singlePET-study and task- as well as stimulation parameterspecific effects can be studied throughout the entirebrain.

■ Abstract Activation studies withpositron emission tomography(PET) and functional magnetic res-onance imaging (fMRI) represent a

Prof. Dr. Andres O. Ceballos-Baumann (�)Dept. of NeurologyKlinikum rechts der IsarTechnische Universität MünchenMöhlstrasse 2881675 Munich, GermanyTel.: +49-89/41 40-46 07Fax: +49-89/41 40-48 67E-Mail: a.ceballos@lrz.tum.de

powerful tool to study the func-tional anatomy of Parkinson’s dis-ease (PD). Activation studies offerthe opportunity to study regionalcerebral function in man in vivounder different conditions with theanalysis of task specific changes inregional cerebral blood flow (rCBF)with PET or in the blood oxygena-tion level dependent (BOLD) effectwith fMRI. The combination ofPET and deep brain stimulation isparticularly attractive to study theeffects of discrete perturbations at

different target structures through-out the basal ganglia-thalamocorti-cal circuitries. The use of rCBF PETand fMRI to study the pathophysi-ology of PD in the motor and sen-sory system and mechanisms ofdopaminergic therapy as well assurgical interventions will be re-viewed.

■ Key words Parkinson’s disease ·deep brain stimulation · basalganglia · fMRI, PET

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Basal ganglia-thalamocortical loops in Parkinson’s disease

Activation studies have been useful to test in PD the in-fluential model of basal ganglia-thalamocortical cir-cuitries derived from animal models of hypo- and hy-perkinetic movement disorders. At least five separateparallel loops have been proposed [2] to form one of theprincipal networks of the brain and to mediate motoractivity, eye movements and behavior [33]. These cir-cuits link the basal ganglia via the ventral and dorsome-dial thalamus to premotor areas (‘motor circuit’), frontalarea 8 (‘oculomotor circuit’), to the dorsolateral pre-frontal cortex (‘DLPFC circuit’), the orbitofrontal cortex(‘OFC circuit’), and the anterior cingulate cortex (‘ACCcircuit’). These loops are thought to be spatially segre-gated based on the findings of retrograde tracer experi-ments in non-human primates. The internal segment ofthe globus pallidus (GPi) and substantia nigra reticulata(SNr) are the major output-relays of the basal ganglia.The GPi projects to discrete cortical motor areas (lateralpremotor cortex, supplementary motor area (SMA), andprimary motor cortex).

The major dorsal putamen output is to SMA, dorsalcaudate output is to dorsal prefrontal areas, and ventralstriatum output is to anterior cingulate and or-bitofrontal cortex [3]. As a consequence, one might pre-dict that dopamine loss as it occurs in typical Parkin-son’s disease (PD) would deafferent these cortical areas,in particular the SMA, as the part of the basal gangliapredominantly affected in PD is the dorsal putamen.

PET [39], Single photon emission computerized to-mography (SPECT) with i. v. 133Xe [40] and recentlyalso fMRI studies [21, 45] examined the above predic-tion by studying movement-associated increases ofrCBF in PD compared to control subjects with a joystickparadigm. The joystick could be moved in four possibledirections. Subjects were asked to freely choose the di-rection of movement each time the pacing tonesounded. As predicted, PD patients showed attenuatedincreases in SMA rCBF compared to age-matched con-trols. In order to see whether striatal-frontal associationarea projections could be functionally reafferented inPD these authors scanned before and after the adminis-tration of dopaminergics as well as intrastriatal graftingof dopaminergic neurons [12, 27, 38, 40, 41]. Reversal ofakinesia was associated with a significant increase inSMA and prefrontal cortex blood flow implicating theseareas in the initiation of volitional movements.

Somatosensory system in Parkinson’s disease

The sensory system was studied in PD based on con-joining experimental and clinical evidence supporting afundamental role of the basal ganglia as a sensory ana-

lyzer engaged in central somatosensory control [7].Based on previously recorded data of somatosensoryevoked potentials, these workers expected deficient sen-sory-evoked activation in cortical areas that receivemodulatory somatosensory input via the basal ganglia.Eight PD patients, eight Huntington’s disease (HD) pa-tients and eight healthy controls underwent repetitiverCBF measurements during two experimental condi-tions: i) continuous unilateral high-frequency vibratorystimulation applied to the immobilized metacarpal jointof the index finger and ii) no vibratory stimulus. PD pa-tients had decreased activation of sensorimotor and lat-eral premotor cortex, secondary sensory cortex, poste-rior cingulate, bilateral prefrontal cortex and basalganglia; in HD, decreased activation of secondary sen-sory cortex, parietal areas, and lingual gyrus, bilateralprefrontal cortex and basal ganglia was found; PD andHD revealed overactivation of ipsilateral sensory corti-cal areas, and insular cortex. The finding that activationincreases in ipsilateral sensory cortical areas may be in-terpreted as an indication of either altered central fo-cusing of sensory input, or enhanced compensatory re-cruitment of associative sensory areas in the presence ofbasal ganglia dysfunction [7].

Compensatory mechanisms in Parkinson’s disease

PET and more recently SPECT as well as fMRI haveshown that PD patients may have a mechanism to com-pensate for the hypofunction in the striatofrontal pro-jections with hyperactivity in other regions. The PETstudy by Samuel et al. [46] looked at rCBF changes asso-ciated with performance of a simple sequence of fingermovements in a group of Parkinson’s disease patientsand a group of control volunteers. Again sequential fin-ger movements in the PD patients were associated witha relative impairment of activation in the mesial frontaland prefrontal areas. However, this was the first study todescribe the presence of relative overactivity in the lat-eral premotor and inferolateral parietal regions. The au-thors suggested that in PD there is a switch from the useof defective striato-mesial frontal to relatively intactparietal-lateral premotor circuits in order to facilitateperformance of complex movements. The authors ar-gued that the parietal cortex as an integrator of differentsensory, motivational and attentional inputs could pro-vide the basis of sensory-guided movement generationin PD without the need for an intact basal ganglia mesialfrontal circuit. A compensatory hyperactivity in theparietal-premotor connections may then explain whythe initiation of movements can be facilitated in PD pa-tients with external cues.

In a more recent PET study, Catalan et al. [9] showedthat the cortical overactivity in the parietal and premo-tor areas seen in PD patients when making sequential

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movements becomes more dramatic when the se-quences are longer. Moreover, the anterior SMA under-activated in all previous studies which activated withself-selected simple movements and finger sequences,also becomes overactive. Catalan et al. concluded thatthe areas related to performing sequences apparentlyhave “to work harder” in Parkinson’s disease in an at-tempt to compensate for the frontal deafferentation sec-ondary to the dopamine deficiency.

The effect of external cues on movement initiationcan be particularly striking in the parkinsonian gait dis-order. Hanakawa et al. [19] investigated with 99mTc-hexamethylpropyleneamine SPECT oxime “paradoxicalgait” induced by visual cues in PD patients during gaiton a treadmill guided by two different visual stimuli: 1)lines orientated transversely to the direction of walk and2) lines parallel to it. PD patients showed marked im-provement of gait parameters while exposed to trans-verse as opposed to parallel lines coupled with enhancedactivation in right lateral premotor cortex. In anothertreadmill experiment [19] with two conditions (1) walk-ing on the treadmill; 2) lying supine) comparing walk-ing-associated rCBF changes with controls PD patientsrevealed relative underactivation in the left medialfrontal area, but also hypoactivity in right precuneusand left cerebellar hemisphere,whereas they showed rel-ative overactivity in the left temporal cortex, right in-sula, left cingulate cortex and cerebellar vermis. The au-thors explained the underactivity in the left cerebellarhemisphere, in contrast to the overactivity in the vermiswith a loss of lateral gravity shift in parkinsonian gait. Incontrast, Rascol et al. found an overactivation in the ip-silateral cerebellar hemisphere with finger-to-thumbopposition motor task in PD patients off medicationduring a SPECT study [42]. Possibly, PD patients recruitin a compensatory mechanism a whole system involvingcerebellar-parietal-premotor loop bypassing by thismeans defective striato-frontal pathways.

fMRI in Parkinson’s disease

Sabatini et al. [45] used fMRI to study the changes in-duced by the performance of a complex sequential mo-tor task in apical cortical areas (nine joint axial slices of5 mm thickness) of six akinetic PD patients in the ‘off ’condition and six normal subjects. The subjects wereresting for 30 s and activating for 30 s with a cognitivelydemanding task consisting of complex sequential move-ments including finger-to-thumb oppositions, fist open-ing and clenching in a specified order. Compared withthe normal subjects, the PD patients exhibited a rela-tively decreased fMRI signal in the rostral part of theSMA and in the right dorsolateral prefrontal cortex.Novel findings relative to PET and SPECT were that thelateral premotor and parietal cortices are not the only

detectable overactive areas in PD but also the caudalSMA, the anterior cingulate and the primary sensori-motor cortices. The authors concluded that apart fromthe lateral premotor and parietal cortices, increasedfMRI signals can be found in other cortical motor areaswhich try to compensate for the functional deficit of thestriatocortical motor loops. Haslinger et al. [21] usedevent-related fMRI with high speed EPI-sequences (sixjoint apical slices parallel with a single slice thickness of0.6 cm covering parietal and most of the frontal cortex).The advantage of an event-related approach is that it re-flects more specifically task-associated changes. Theyscanned eight PD patients in the ‘off ’ and ‘on’ conditionbefore and after levodopa intake in one single study ses-sion and age-matched healthy volunteers while per-forming freely selected joystick movements. The joy-stick was linked to a MRI compatible monitoring systemwhich allowed the coupling of movement with fMRIdata. Patients both off and on levodopa showed signifi-cant underactivity in rostral SMA in contrast to in-creased activation in M1 and lateral premotor cortex bi-laterally. Overactivation of the lateral premotor cortexhas also been shown in a block design fMRI study [45]and PET [10, 46] studies on complex finger movements.Levodopa led to a significant signal increase in rostralSMA, whereas patients before levodopa showed highersignals in M1/lateral premotor, superior parietal andprefrontal cortex bilaterally. Bilateral movement associ-ated signal increase in the primary sensorimotor cortexas shown now in three fMRI studies in PD [21, 25, 45]was not detected in previous PET and SPECT studies.This may reflect diffuse disinhibition of primary motorcortex possibly representing the neural substrate ofrigidity.

The unanimously found underactivation of the SMAand its reversal with the improvement with akinesia infMRI [21, 25, 45] and previous PET and SPECT studies[12, 21, 26, 28, 38–41, 45, 46] fits well with akinesia in thecurrent model of basal ganglia thalamocortical cir-cuitry. However, the issue appears to be more complex.Underactivation of the mesial frontal, especially the ros-tral SMA as a hallmark of akinesia, was observed inthese studies during simple movements,especially whenthe movement or its timing is chosen by the subjectsthemselves (self initiated simple finger movements [26])when movements are unskilled, automated (simple fin-ger sequences [40, 45, 46] and ballistic joystick move-ments [21, 39].

A lack of SMA underactivation in PD was reported intwo fMRI studies which specifically included attentionaland working memory task in their paradigm. PD pa-tients failed to increase the activation in prefrontal,pari-etal and paracingulate cortex, and the supplementarymotor area (SMA) relative to the age-matched controlsin a fMRI study with a paced overlearned motor se-quence task when PD patients were asked to attend to

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their actions [44]. In light of these results, the commonfinding of underactivation in PD of the SMA during sim-ple movements may be interpreted as a hypofunction inthe allocation of attentional resources or, put in otherwords, in a deficit in the attentional modulation of ef-fective connectivity between the prefrontal, premotorcortex and SMA. This explanation is further supportedas these authors analyzed the effects of experimentalmanipulation on effective connectivity within a speci-fied model of interconnections between four primaryand non-primary motor areas (premotor cortex, SMA,primary motor cortex, prefrontal cortex) using a sophis-ticated statistical approach, structural equation model-ling. Attention to action did not increase the effectiveconnectivity between prefrontal cortex and both the lat-eral premotor cortex and the SMA in PD patients. Roweet al. concluded that this deficit indicates a context-spe-cific functional disconnection between the prefrontalcortex and the SMA and premotor cortex in PD [44].Ac-cording to this study the question whether the SMA inPD is underactive depends on the appropriate recruit-ment of attentional resources required to perform thepertinent actions: PD patients appear to compensatetheir deficit by already directing maximal recruitmentfor automatic finger sequences.

A different explanation which takes into account thatthe dopaminergic deficit in PD primarily affects dorsalputaminal and less so caudate function is provided by afMRI which clearly separated cognitive and motor con-ditions in their design. Mattay et al. [32] studied the ef-fects of dopaminergic therapy on neural systems, sub-serving working memory and motor function werestudied in ten early onset PD patients with fMRI, duringa relatively hypodopaminergic state (i. e., 12 hours aftera last dose of dopamimetic treatment), and again duringa dopamine-replete state under three conditions: aworking memory task, a cued sensorimotor task andrest. The cortical motor regions activated during themotor task showed greater activation during thedopamine-replete state; however, the cortical regionssubserving working memory displayed greater activa-tion during the hypodopaminergic state. Interestingly,the increase in cortical activation during the workingmemory task in the hypodopaminergic state positivelycorrelated with errors in task performance, and the in-creased activation in the cortical motor regions duringthe dopamine-replete state was positively correlatedwith improvement in motor function. These results sup-port evidence from basic research that dopamine mod-ulates cortical networks subserving working memoryand motor function via two distinct mechanisms: ni-grostriatal projections facilitate motor function indi-rectly via thalamic projections to motor cortices,whereas the mesocortical dopaminergic system facili-tates working memory function via direct inputs to pre-frontal cortex. The results are also consistent with evi-

dence that the hypodopaminergic state is associatedwith decreased efficiency of prefrontal cortical informa-tion processing and that dopaminergic therapy im-proves the physiological efficiency of this region.

Pallidotomy and deep brain stimulation in the globus pallidus internus (GPI)

The physiological background of neurosurgery fortreatment of parkinsonian akinesia is based on theabove mentioned model of basal ganglia connectivity[3].According to this model, the nigrostriatal dopaminedeficit is presumed to lead to overactivity of STN andGPi. The rationale for pallidotomy is that it may inter-rupt excessive inhibitory output from the basal gangliasecondary to the loss of dopamine and hence facilitatethalamofrontal projections. PET activation studies werein accord with this prediction: an increase in movement-related cortical activity in SMA after pallidotomy(Fig. 1) was a common finding across laboratories de-spite apparent differences in surgery, employed motortasks, PET scanners and image analysis methods [11, 18,47].

An 18F-fluorodeoxyglucose (FDG) PET study of co-variance patterns of resting glucose metabolism in PDpatients demonstrated increased glucose metabolismfollowing pallidotomy in ipsilateral dorsal prefrontalcortex, primary motor cortex and lateral premotor cor-tex along with decreases in thalamic and lentiform me-tabolism [17]. No relative increases in resting SMA me-tabolism were detected in that study. However, in aresting rCBF PET study (though patients had to countsilently in both conditions) on the effects of GPi stimu-lation, Davis et al. [15] showed increased rCBF in rostralSMA compared to baseline without stimulation. Inter-estingly, a case report on bilateral DBS of both GPis ofone patient with severe idiopathic generalized dystoniaresulting in immediate improvement of dystonia re-duced PET activation bilaterally in the primary motor,lateral premotor, supplementary motor, anterior cingu-late, and prefrontal areas and ipsilaterally in thelentiform nucleus [29].

Dopa-induced dykinesias

Dopa-induced dyskinesias were studied in blood flowstudies with PET [24] and SPECT with i. v. 133Xe activa-tion studies by Hershey et al. with PET started from thepremise that improvement in motor function and dopa-induced dykinesias after pallidotomy is inconsistentwith the current model of basal ganglia connectivity,and investigated with PET rCBF responses to levodopa-challenges in six PD patients with dopa-induced dyski-nesias (DID), ten patients without DID, 17 dopa-naive

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PD patients, and 11 normals at rest. The dose of lev-odopa was chosen to produce clinical benefit withoutinducing DID. These workers found that the DID grouphad a significantly greater response in ventrolateral thal-amus than the other groups associated with decreasedactivity in primary motor cortex.The authors concludedthat these findings are consistent with increased in-hibitory output from the GPi to thalamus after levodopaadministration. This in turn would provide a physiolog-ical explanation for the clinical efficacy of pallidotomyand the facilitation of thalamofrontal projections withmotor overactivation in DID patients as shown in aSPECT study [43].

Thalamic deep brain stimulation in the nucleusventralis intermedius (VIM) and mechanisms of deep brain stimulation

Parker et al. were the first to investigate VIM stimulationin parkinsonian tremor [36]. They scanned PD patientsin two conditions: absence of tremor under VIM stimu-lation (130 Hz) and presence of resting tremor withstimulators off (Fig. 2). They found decreases duringstimulation with absence of tremor in somatosensorycortex, SMA, caudate, vermis ipsilateral to stimulationand in contralateral cerebellar grey nuclei. They con-cluded that parkinsonian resting tremor shared a com-mon network of brain structures with repetitive volun-tary movement. Deiber et al. studied the effects of VIMstimulation on tremor in PD patients in three condi-tions: absence of tremor under effective (130–185 Hz),ineffective (50–65 Hz) and no stimulation [16]. These

authors chose to scan lower parts of the brain since theywere mainly interested in the effects of VIM stimulationon cerebellar activity. Their field of view only includedlower parts of primary motor cortex. Their main findingwas that suppression of tremor was associated with a de-crease of rCBF in the cerebellum. As pointed out byStrafella et al. [49], this reduction in cerebellar rCBFcould suggest an antidromical stimulation of cerebel-lothalamic axons. However, the main problem in studiesof VIM stimulation in parkinsonian rest tremor are theinterfering effects that cause problems in interpretingstimulation associated rCBF changes: in fact, switchingVIM-stimulation off in PD patients immediately leads toa coarse resting tremor and “rebound” phenomenon. Asalready discussed by Deiber at al. [16] and Parker et al.[36] rCBF changes with effective VIM stimulation seenin PD could, therefore,well represent changes associatedwith alterations in proprioceptive and kinaesthetic in-put.

The functional effects underlying deep brain stimu-lation (DBS) are not well understood. The simplest ex-planation for the mechanism of action is that neuronsstimulated with high frequencies behave like lesionedneurons, since the clinical effects of lesioning and stim-ulation are comparable.A direct activating effect of DBSon neuronal pathways could also be postulated as amechanism of action like activation of parallel runningexcitatory and inhibitory projections is a commonly ac-cepted mechanism of electrical stimulation.In a study inessential tremor patients [14] the authors hypothesizedthat VIM stimulation would lead to rCBF changes inVIM projection areas, namely motor [4, 5, 50] and pari-eto-insular vestibular cortex (PIVC, area retroinsularis)

Fig. 1 Surface renderings of the cerebral hemi-spheres from the patient before and after pallido-tomy with the PET activation rCBF increases super-imposed on the individual’s own MRI. Theorange-yellow areas show voxels to a depth of 10 pix-els that are statistically significant above a thresholdof omnibus p < 0.001 projected on to the cortical sur-face. Note the change in the activation pattern afterpallidotomy with more extensive activation of lateralpremotor cortex (PMC), supplementary motor area(SMA), parietal association areas and dorsal pre-frontal cortex (DLPFC) while the patient is performingthe movements [11]

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[1, 22, 23]. Regional CBF was measured during three ex-perimental conditions: during = 130 (effective), 50 Hz(ineffective) and without VIM stimulation at rest. Tostudy patients with essential in contrast to parkinsoniantremor at rest has the advantage of keeping motor activ-ity in all three scanning conditions identical. Effectivestimulation was associated with rCBF increases in mo-tor cortex ipsilateral to the side of stimulation. Retroin-sular (parieto-insular vestibular) cortex showed rCBFdecreases with stimulation. If functional ablation ofVIM neurons was the main mechanism of action, thenone would expect similar PET findings after thalamo-tomy. But rCBF increases in the primary motor cortexwere not observed after thalamotomy where destroyingorthograde excitatory thalamo-cortical projections in-duced significant reductions in rCBF of the correspond-ing ipsilateral motor cortex [6]. The authors concludedthat the beneficial effects of VIM stimulation are associ-ated with increased synaptic activity in the motor cor-tex. This finding differentiates thalamic stimulationfrom thalamic lesions [6] and is likely to represent anonphysiologic activation of thalamocortical projec-tions incomprehensible to cortical target neurons in-hibiting the abnormal oscillatory mechanisms responsi-ble for tremor. Retroinsular rCBF decreases suggest aninteraction of VIM stimulation on vestibulo-thalamic-cortical projections that may explain dysequilibrium, acommon and reversible VIM stimulation associated sideeffect.

The DBS-specific effect of activation of VIM efferentthalamocortical projections to the sensorimotor cortexas well as the unknown changes at the target site of theelectrode were reported in a further PET study, again inET patients to avoid the confounding effects of resttremor [20]. Parametric PET analyses allowed to char-acterize rCBF responses as linear and nonlinear func-tions of the experimentally modulated stimulus (= vari-able stimulator setting). Variations in voltage andfrequency of thalamic stimulation have differential ef-fects in a thalamo-cortical circuitry. Increasing stimula-tion amplitude was associated with a linear rise in rCBFat the thalamic stimulation site, but with a nonlinearrCBF response in the primary sensorimotor cortex(M1/S1). The reverse pattern in rCBF changes was ob-served with increasing stimulation frequency. These re-sults indicate close connectivity between the stimulatednucleus (VIM) and primary sensorimotor cortex. Like-wise, stimulation parameter-specific modulation occursat this simple interface between an electrical and cere-bral system and suggests that the scope of DBS extendsbeyond an ablation-like on-off effect: DBS could ratherallow a gradual tuning of activity within a neuronal cir-cuit [20].

Fig. 2 rCBF changes correlated with voltage of thal-amic ventrointermediate (VIM) nucleus stimulationaround the stimulating electrode in VIM (a–c) andthe thalamocortical projection, the primary sensori-motor cortex (d–f). a Parameter estimates for corre-lations of rCBF with the first and second order expan-sion of individual stimulation parameters show abetter correlation for the first order covariate in thal-amus for each patient. b Plots of individual and aver-aged (‘mean’) fitted rCBF responses against steps ofincreasing voltage and c an individual example of thefitted and ‘adjusted’ rCBF data show a ‘linear ’ in-crease of rCBF with increasing amplitude in VIM. Inthe motor cortex, d parameter estimates as well as eindividual and mean fitted and f adjusted responsesshow a nonlinear correlation to increasing amplitude[20]

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Deep brain stimulation in the nucleussubthalamicus (STN)

Like surgery targeting the GPi, STN stimulation aims toreduce the overactivity of GPi by decreasing overactiveexcitatory STN projections which otherwise reinforcethe inhibitory GPi overactivity directed towards thethalamus. Therefore, reduction of STN overactivitywould be expected to reduce inhibitory GPi output tothalamic relay nuclei and in turn disinhibit the ventralthalamus and facilitate thalamic excitation of premotorand prefrontal cortical areas (Fig. 3). In accord with thisprediction, two PET studies showed enhanced move-ment-associated activation in premotor areas and dor-sal prefrontal cortex, while akinesia improved duringSTN stimulation [13, 30]. In both studies movement-as-sociated increased activation was centered around theSMA, though the peak changes in mesial frontal cortexwere more rostral (pre SMA) in one study [13] and theseauthors also described enhanced activation of the lateralpremotor cortex ipsilateral to stimulation like in the pre-and post-pallidotomy studies [11, 18]. It is likely that dif-ferences in patient selection (patients were more af-fected in one study [30]), stimulation parameters andslight variation in targets within the STN may accountfor the differences in the frontal pattern of movement-associated rCBF changes. Not predicted beforehand wasthe observation in both STN studies [13, 30] that STNstimulation induced robust ipsilateral resting rCBF de-creases in motor cortex which is the inverse to the effects

during VIM stimulation [14, 20]. The decrease in motorcortex activity during STN stimulation was explainedeither as a consequence of the improvement in premo-tor function or rigidity, alternatively as a consequence ofantidromical stimulation of projections from motorcortex to the STN.

The STN has generally been considered as a relay sta-tion within frontal-subcortical motor control circuitry.Little is known about the influence of the STN on cogni-tive networks. Clinical observations and animal studiessuggest that the STN participates in non-motor func-tions [35]. Changes in rCBF associated with a responseconflict task (Stroop task) in PD patients on and off bi-lateral STN-stimulation were studied using PET [48].The Stroop task requires subjects to name the color ofink of color words printed in incongruent color ink. Aspredicted, deep brain stimulation in the STN decreasedrCBF responses in the anterior cingulate cortex (ACC)during the Stroop task while impairing at the same timetask performance (Fig. 4). The peak of the differences inactivation fell well within the part of the ACC associatedwith cognitive function [8]. Decreased activation wasalso located in the ventral striatum, the structure receiv-ing input from the ACC in the current model of basalganglia organization. The angular gyrus showed higher

Fig. 4 Projections in the stereotactic space of Tailarach and Tournoux of impairedactivation during the stimulator on compared to the stimulator off associated withthe Stroop effect. A sagittal view of an individual MRI is depicted with an overlay ofthe focus of impaired activation in the anterior cingulate cortex. A highly simplifieddiagrammatic version of the striato-anterior cingulate cortex circuit is shown withone important STN afferent and efferents (green = excitatory; red = inhibitory).The subthalamic nucleus can be regarded as a ‘control structure’ lying alongside themain stream of information processing and because of its widespread efferent pro-jections, the subthalamic nucleus exerts its driving effect on most components ofthe basal ganglia. This way STN stimulation may perturbate the circuit in new andunexpected situations requiring non-automated behavior and disruption of basalganglia input at the level of the STN may lead to inflexibility of mental and motorresponses as shown in the Stroop task. Activation differences were localized in theleft anterior cingulate cortex (BA 24/32, x = –10, y = 28, z = 15) and the right ven-tral striatum (x = –20, y = 9, z = –11). X, Y, Z express the position of the voxel inmm relative to the anterior commissure (AC) in stereotactic space. X lateral distancefrom the midline (- right, + left), Y anteroposterior distance from the AC (+ ante-rior, – posterior), Z height relative to the AC line (+ above, – below) [48]

Fig. 3 Areas with statistical significant enhanced activation in rostral SMA andpremotor cortex (ipsilateral to stimulation and contralateral to movement) in thepatient group during STN stimulation shown as SPM projections with a cutoff ofp < 0.001 while performing random joystick movements at 0.33 Hz projected on avolume rendered individual 3D brain image. Adjusted rCBF of the peak enhancedactivation in premotor cortex ipsilateral to the stimulating electrode at rest (R) andduring the activating condition (A) ON and OFF STN-stimulation is depicted [13]

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activation during on-stimulation compared to the off-state. The angular gyrus is associated with encoding ofwords [34, 37]. The increased activation during stimula-tion therefore, corresponds most likely to difficulties insuppressing the habitual response, that is word process-ing when patients had actually to name the color of thecolor word. Alternatively, during off-stimulation ACCmight effectively modulate language processing in theangular gyrus resulting in decreased activation com-pared to the on-state.

The differential impact of STN stimulation on cogni-tive and motor circuitry in two PET studies using sim-ple movements [13] and a response conflict task as acti-vating paradigm [48], respectively, supports the twoopposite predictions of the so-called paradox of stereo-

tactic surgery in PD [31]. The motor system devoid ofthe important basal ganglia input structure STN couldcontinue to function in routine, predictable and auto-matic movement. ‘Releasing the brake’ on frontal func-tion with STN stimulation improves aspects of motorfunction. However, in new and unexpected situations re-quiring non-automated behavior, disruption of basalganglia input at the level of the STN may lead to inflexi-bility of mental and motor responses as shown in theStroop task.

■ Acknowledgments This work was supported by the DFG SFB 462TPC3 and Ce 41–1, KKF-Grant and the Deutsche Parkinson Vereini-gung.

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