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Bimanual Recoupling by Visual Cueing in CallosalDisconnectionRüdiger J. Seitz a , Raimund Kleiser a , Cathrin M. Bütefisch b , Silke Jörgens a , OliverNeuhaus a , Hans-Peter Hartung a , Hans-Jörg Wittsack c , Volker Sturm d & Manuel M.Hermann ea Department of Neurology, University Hospital Düsseldorf , Düsseldorf, Germanyb Neurological Therapy Center Düsseldorf , Düsseldorf, Germanyc Institute of Diagnostic Radiology, University Hospital Düsseldorf , Düsseldorf, Germanyd Department of Stereotactic Neurosurgery, University Hospital Köln , Köln, Germanye Institute of Neuropathology, University Hospital Köln , Köln, GermanyPublished online: 16 Aug 2010.

To cite this article: Rüdiger J. Seitz , Raimund Kleiser , Cathrin M. Bütefisch , Silke Jörgens , Oliver Neuhaus , Hans-Peter Hartung , Hans-Jörg Wittsack , Volker Sturm & Manuel M. Hermann (2004) Bimanual Recoupling by Visual Cueing inCallosal Disconnection, Neurocase: The Neural Basis of Cognition, 10:4, 316-325, DOI: 10.1080/13554790490505373

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DOI: 10.1080/13554790490505373

Neurocase

Bimanual Recoupling by Visual Cueing in Callosal Disconnection

Rüdiger J. Seitz1, Raimund Kleiser1, Cathrin M. Bütefisch2, Silke Jörgens1, Oliver Neuhaus1, Hans-Peter Hartung1, Hans-Jörg Wittsack3, Volker Sturm4 and Manuel M. Hermann5

1Department of Neurology, University Hospital Düsseldorf, Düsseldorf, Germany, 2Neurological Therapy Center Düsseldorf, Düsseldorf, Germany, 3Institute of Diagnostic Radiology, University Hospital Düsseldorf, Düsseldorf, Germany, 4Department of Stereotactic Neurosurgery, University Hospital Köln, Köln, Germany, and 5Institute of Neuropathology, University Hospital Köln, Köln, Germany

Abstract

The cerebral control of bimanual movements is not completely understood. We investigated a 59-year-old, right-handed man who presented with an acute bimanual coordination deficit. Magnetic resonance imaging showed a lesion involving the entire corpus callosum, which was found on stereotactic biopsy to be an ischemic infarct. Paired-pulse transcranial magnetic stimulation indicated that the patient had a lack of interhemispheric inhibition, while intracortical inhibition in motor cortex of either side was normal. Functional magnetic resonance imaging showed activation of the left SMA, the bilateral motor cortex and anterior cerebellum during spontaneous bimanual thumb-index oppositions, which were uncoupled as evident from simultaneous electromyographic recordings. In contrast, when the bimanual thumb-index oppositions were cued by a visual stimulus, the movements of both hands were tightly correlated. This synchronized activity was accompanied by additional activations bilateral in lateral occipital cortex, dorsal premotor cortex and cerebellum. The data suggest that the visually cued movements of both hands were recoupled by action of a bihemispheric motor network.

Introduction

The coordination of activity in both hands is an ability ofhumans essential for managing a large number of target-ori-ented, daily activities such as closing buttons, retrievingobjects from a drawer and driving a car. In many of thesehand-object interactions the hands perform synergistic move-ments with the non-dominant hand holding the object in theoptimal position and the dominant hand executing the task.But the opposite can also take place as for instance when thenon-dominant hand turns a page in a book or newspaperwhile the dominant hand stabilizes the object. Thus, the con-joint actions of both hands are tightly coupled both in termsof their spatial relation and temporal characteristics. In fact,bimanual coordination is a highly developed skill that usuallydoes not require attentive control (Kazennikov et al., 1994;,Temprado et al., 2002). Apart from bimanual synergies,when both hands assume a complimentary function, there arealso other types of bimanual movements. These include thebilateral performance of continuous movements, for example,during crawling, and of discontinuous movements such asplaying piano.

A number of recent neuroimaging studies have shown thata symmetric bihemispheric circuit is activated in relation to

bilateral limb movements, including the sensorimotor cortex,the supplementary motor area (SMA), the dorsal premotorcortex and the anterior cerebellum (for a review, see Wenderothet al., 2004). It is, however, unclear if there is a key structuregoverning interlimb coordination or if the entire network isrequired. In this regard, studies of neurological patients offeran important opportunity to understand brain function, sincefocal brain lesions are thought to interfere with the criticalnode in cerebral circuits, while functional imaging often failsto show the critical node within the entire activated circuit(Seitz, 2002). In fact, lesions of the lateral premotor cortexhave been shown to interfere with bilateral coordination ofproximal movements of the arms as well as of the legs duringlocomotion (Freund and Hummelsheim, 1985). Moreover,there are a few reports on patients with lesions in the frontalmidline structures providing evidence that the SMA and cin-gulate are of critical importance for bimanual coordination(Dick et al., 1986; McNabb et al., 1988; Feinberg et al., 1992;Stephan et al., 1999-b). However, lesions of the corpus callo-sum also result in bimanual coordination deficits as foundwith transcranial magnetic stimulation (TMS) in patients withmultiple sclerosis (Larson et al., 2002; Schmierer et al., 2002)

Correspondence to: Dr. Rüdiger Seitz, Department of Neurology, University Hospital Düsseldorf, Moorenstrasse 5, 40591 Düsseldorf, Germany. Tel: +49-211-81-18974; Fax: +49-211-81-18485; e-mail: seitz@neurologie.uni-duesseldorf.de

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Bimanual coordination deficit 317

and callosal infarcts (Serrien et al., 2001). Specifically, patientswith acquired callosal dysfunction are severely hamperedwhen motor tasks place significant demands on the precisetiming of bimanual coordination, even when investigatedmonths after lesioning (Franz et al., 2000; Eliassen et al.,2000; Serrien et al., 2001). Patients with focal brain lesionsin the frontomesial areas are extremely rare. For instance,patients with infarcts in the anterior cerebral artery, whichsupplies the SMA and midcingulate, constitute fewer than2 percent of stroke patients although they face the same riskfactors as other types of ischemic brain infarcts (Kumralet al., 2002). Patients with acquired lesions or infarcts of thecorpus callosum are even less frequent. Here we report apatient with a severe disabling bimanual coordination deficitdue to a complete infarction of the corpus callosum. We willdemonstrate that visual cueing allowed him to synchronizethe movements of both hands and that a premotor-cerebellarcircuit that is known to be important for visual and temporalguidance of movements was involved (Jancke et al., 2000a;Debaere et al., 2003).

Methods

Patient

The 59-years-old man presented with episodes of inability tomove his left leg accompanied by an alien limb sensation ofthis leg for four weeks. In addition, there was a speech arrest.These episodes lasted for about 30 minutes and were consid-ered as focal epileptic seizures since they ceased after treat-ment initiation with oxcarbacepine. Since the first episode,the patient suffered from a continuing bimanual coordinationdeficit. This deficit prevented him from switching objectsbetween his hands and also, for example, from reading news-papers. He would tear the pages when trying to turn themover since he could not release the grip of either hand. Hewould even fail in these activities when carefully watchinghis movements. His prior history was unremarkable with theexception of a 10-year history of insulin-dependent diabetesmellitus and treated arterial hypertension. On neurologicalexamination he was ambulatory but showed a slowing of hisleft leg and reduced swinging movements of his arms duringwalking. Alternating hand movements were slowed on theleft side. The muscle tendon reflexes were symmetric, but theplantar response was extensor on the left. He could not per-form bilateral simultaneous and alternating arm, finger andleg movements. In fact, when asked to perform repetitivemovements of the thumb and index fingers of both hands,he would do this at approximately 2 Hz with his right handbut at a considerably higher frequency (approximately 4 Hz)with his left hand. This was the case both when he had hiseyes open or closed. Sensation was normal apart from adiminished vibration sense of two of eight possible points onhis toes.

The patient was right-handed as assessed with the Edin-burgh questionnaire (Oldfields, 1971). Neuropsychological

testing involved tests of verbal fluency (Aschenbrenner et al.,2000), Wechsler and Rivermead memory scales (Wilsonet al., 1985; Härting et al., 2000), attention (Meyers andMeyers 1995) and executive functions (Wilson et al., 1996)as summarized in Table 1. The patient showed a left-handapraxia but no aphasia, alexia, acalculia, agnosia on eitherside of his body and no memory deficit. Tactile objectnaming was normal with either hand. However, he performedin the low average range on tests of executive functioningand showed subnormal errors in design fluency. In addition,his divided attention and tonic alertness were below thenormal range. Neuropsychological test results are summa-rized in Table 1.

Magnetic resonance imaging showed a lesion involvingthe entire corpus callosum and extending into the whitematter underlying right cingulate gyrus (Fig. 1). There wasno pathological contrast enhancement. Doppler sonographyand intraarterial angiography showed no relevant extra- orintracranial arterial stenosis. Since we expected the patientto suffer from a neoplastic brain lesion, a stereotactic biopsywas performed to clarify the nature of the lesion. Histology,however, showed that the lesion was a cerebral infarctat the stage of advanced macrophagic invasion (Fig. 2).The infarct was considered to be of microvascular originbased on a long-standing insulin-dependent diabetes melli-tus, arterial hypertension and the newly diagnosed hyper-lipidemia.

Table 1. Neuropsychological assessment of the patient

Neuropsychological assessment Performance

Attention (Zimmermann and Fimm, 1993)

Tonic Alertness (RT ms) 309.0 (PC 12)Phasic Alertness (PC 54)Selective Attention (RT ms) 573.5 (PC 46)Errors 0 (PC >46)Divided Attention (RT ms) 839.0 (PC 4)Errors 6 (PC 4)Cognitive Flexibility (RT ms) 989.0 (PC 31)Errors 5 (PC <50)

MemoryRey-Osterrieth Complex Figure

(delayed)12 items (control scores:

18.8, SD = 7.4)Story immediate recall (RBMT) 10.5 items ( PC 78.1-84.4)Story delayed recall (RBMT) 8.5 items (PC 71.0- 74.2)Digit span forward (WMS) 6 (PC 18)Digit span backward (WMS) 5 (PC 31)Block span forward (WMS) 7 (PC 37)Block span backward (WMS) 5 (PC 24)

Executive FunctionsBehavioural Assessment of Dysexecutive

Syndrom (Wilson et al., 1996)Total Profile Score: 16

“Low Average”Verbal fluency (2 min. formal lexical) 22 words (PC = 50)Verbal fluency (2 min. semantic) 28 words (PC = 18)5-Point Test (total) 32 (normal score: 37.7, SD = 9.7)Errors 9 (normal score: 1.9, SD = 2.8)Florida Apraxia Screening Left sided apraxia

RBMT: Rivermead Behavioral Memory Test, WMS: Wechsler MemoryScale, PC: percentile, SD: standard deviation, RT: reaction time.

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Control subjects

Two healthy men aged 46 and 69 served as controls for thefMRI study. They were right-handed, free of neurological orpsychiatric disease and normal on physical examination.

Transcranial Magnetic Stimulation

Single-pulse transcranial magnetic stimulation (TMS) wasperformed to investigate the central motor conduction velo-city of the fastest corticospinal motor neurons projecting tothe first dorsal interosseus and anterior tibial muscles oneither side as described in detail previously (Benecke et al.,1991; Kloten et al., 1992). In brief, TMS was applied with aNovametrix Magstim 200 HP (Magstim Company, UK)using a circular coil with an outer diameter of 12 cm for thefirst dorsal interosseus muscle (FDI) and an angulated coil forthe anterior tibial muscle (TA), respectively. A stimulationstrength of 1.5 times the threshold that produced a visiblemotor evoked potential (MEP) of the resting muscle wasapplied. Surface adhesive electrodes were used for recordingof the evoked electromyographic activity. The amplitude ofthe largest MEP of five trials was determined from the differ-ence between the maximum and minimum of each trial. Thisamplitude was expressed as a percentage of the evoked mus-cle action potential after supramaximal stimulation of thesupplying peripheral nerve. The central conduction time wascalculated as the onset latency of the fastest of five corticallyevoked MEPs minus the peripheral conduction time aftermagnetic root stimulation. The postexcitatory inhibition wasdetermined from the MEPs evoked in the muscles duringvoluntary contraction at 10% of maximal isometric contrac-tion as detailed elsewhere (Roick et al., 1993; von Giesenet al., 1994). The time of electromyographic silence after the

Fig. 1. Infarction of the corpus callosum and the adjacent part of the right anterior cingulate as shown in four consecutive FLAIR MR-images.

Fig. 2. Histological section of the stereotactic brain biopsy showing macroph-ages invading necrotic brain tissue characteristic for subacute brain infarction.Hematoxylin-eosin staining, 400 x magnification.

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Bimanual coordination deficit 319

MEP until the reoccurrence of electromyographic back-ground activity determined the postexcitatory inhibition.

Paired-pulse TMS was used to investigate the corticalexcitability of motor cortex as described in detail previously(Bütefisch et al., 2003). The intracortical inhibition wastested by paired pulse TMS at an interstimulus interval of 2ms for different intensities of the subthreshold conditioningtranscranial magnetic stimulus (CS). CS intensity wasexpressed as a percentage of the motor threshold. Pairedpulses were intermixed with single test and conditioningpulses. Five paired pulses, five single test and five condition-ing pulses were given. The amplitude of motor-evokedpotentials (MEP) elicited by the paired-pulse stimulation wasexpressed as the ratio of the mean MEP amplitude evoked bysingle test pulses. In addition, interhemispheric excitabilitywas investigated using paired-pulse TMS with at interstimu-lus intervals of 2, 8 and 10 ms where the conditioning stimu-lus was applied to the motor cortex of one hemisphere andthe test stimulus to the homologous area of the contralateralmotor cortex (Ferbert et al., 1992). For each interstimulusinterval, 10 paired-pulses were given. Intensity of the condi-tioning and test pulse was set to produce an MEP amplitudeof about 1 mV.

Functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) of bloodoxygen level decreases (BOLD) related to finger movementactivity was performed with echoplanar imaging EPI usinga 1.5T MR scanner (SIEMENS, Erlangen, Germany). Imag-ing parameters were TR 4s, TE 66 ms, flip angle 90deg, thevoxel size 3x3x4.4 mm. Twenty-eight consecutive slices ori-ented parallel to the AC-PC plane were acquired, coveringthe whole brain. Image analysis was performed using thefMRI analysis software package Brain Voyager 4.9 (BrainInnovation, Maastricht, The Netherlands). The MR imageswere realigned to correct for head movements between scans.Pre-processing of the volume time courses involved Gaussianspatial smoothing (FWHM = 6mm), removal of linear trendsand temporal high pass filtering with a 3-minute cut-off toremove slow periodic drifts. To enhance power, the imagedata of the control subjects were pooled.

During scanning the electromyographic activity (EMG) wasrecorded simultaneously using surface electrodes attached tothe first dorsal interosseus muscle of either side. EMG activ-ity was recorded at a rate of 1 kHz, amplified using an MR-compatible amplifier (IED, Hamburg, Germany), filteredwith a bandpass filter (1 Hz to 1 kHz) and stored in digital for-mat for off-line analysis. Analysis of the EMG activity datawas performed in the time domain using the software packageMatlab 6.1. The signals were filtered with a 5th order 70 Hzhigh pass filter to eliminate linear trends and smoothed with aGaussian filter of FWHM = 10 ms. All data with superim-posed artefacts due to MR gradient signals were removed.Cross-correlation analysis was performed between the mus-cles of the left and right hand using the EMG data of the total

MR scanning time. The sequence was normalized so that theauto-correlations at zero lag are identically 1.0.

Behavioral task

The active tasks consisted of repetitive thumb-index opposi-tions. These movements had to be performed separately witheither hand and in a third block conjointly while the subjectshad their eyes open in a self-paced and a visually pacedmanner, respectively. Thus, there were six conditions of 24-second duration for each hand. In the paced blocks, a letterwas projected onto a screen within the MR gantry in front ofthe subjects. It served as a visual stimulus and was used toinstruct the subjects to perform the desired task. There wereblocks in which subjects were prompted to execute move-ments by letters paced at a frequency of 1 Hz. In the non-pacedblocks, the subjects were required to execute these move-ments in a self-paced manner at approximately 1 Hz. In thecontrol condition, the subjects were instructed to rest, againhaving their eyes open. The six repetitions of each block werepseudorandomized. Before conducting the fMRI scans, thetask was explained to the subjects who were then asked toindicate that they had understood the instructions.

Results

In the patient the recordings of the electromyogram showedhigh frequency bursts during the self-paced thumb-indexopposition movements of either hand. Similarly, when bothhands were moved together, there was a high number ofEMG bursts corresponding to roughly 2Hz movements forthe right hand and an almost continuous EMG activity, corre-sponding to a high rate of forceless finger movements ofmore than 4 Hz in the left hand (Fig. 3). In contrast, duringthe visually paced conditions, both the unilateral and thebimanual thumb-index oppositions were well timed, showingbursts of similar shape for both hands at a rate of 1 Hz. Con-sequently, there was no correlation of the EMG activity ofboth hands during the self-paced thumb-index oppositionmovements (Fig. 3). However, when the movements of thepatient were visually paced, the patient performed the thumb-index oppositions at the paced rate of 1 Hz, showing a tightcorrelation of the EMG activity between both hands (Fig. 3).In contrast, the control subjects showed a sharp peak of corre-lated EMG activity both during visually paced and self-pacedopposition movements of both hands. The normalized corre-lation of EMG activity during visual pacing in the patientindicated a synchronization of the bimanual thumb-indexoppositions similar to the performance in the controls.Furthermore, the localization of the peak of correlation atorigin indicated that there was no phase shift between thetwo hands, suggesting an in-phase re-coupling of the fingermovements.

The fMRI studies showed a lateralized activation patternrelated to the thumb-index oppositions of either hand both in

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the patient and the control subjects as expected for distalmovements from previous studies (Schlaug et al., 1996; Seitzet al., 2000; Nirkko et al., 2001). This pattern involved thecontralateral sensorimotor cortex, the supplementary motorarea and the ipsilateral anterior cerebellum in the self-pacedconditions. In the visually paced conditions, there was addi-tional activation bilateral of the occipito-temporal cortex,probably representing human MT area both in the patient andthe controls. During bilateral visually paced movements, theactivation patterns also became bilateral, with a prominentinvolvement bilateral of the premotor cortex. Contrastingthe images recorded during the visually paced bilateralmovements with the self-paced bilateral movements wasexpected to show the additional activation related to coordi-nating finger movements in relation to the visual cue. Here,

different patterns became evident between the patient and thecontrols (Fig. 4). In the patient, there was a strong bilateralactivation of the presumable visual area V5, dorsal premotorcortex and the anterior lateral cerebellum in a bilateralsymmetric pattern. In contrast, in the healthy controls, therewas some activation along the intraparietal sulcus, preferen-tially on the left, of the right visual area V5 and in the leftanterior parasagittal cerebellum. As expected, activationrelated to movement activity was cancelled out both in thepatient and in the controls (Fig. 4). By inverting the contrastthere was no enhanced activity in the self-paced condition ascompared with the visually cued condition.

In the patient, single pulse TMS showed normal MEPswith normal central latencies for the first dorsal interosseus(FDI) and anterior tibial (TA) muscles on both sides (Table 2).Also, postexcitatory inhibition was in the normal range forboth muscles on either side (Table 2). Paired-pulse TMSshowed that the conditioned MEPs evoked in either hemi-sphere decreased in amplitude with increasing strength of theconditioning stimulus (Fig. 5a). This indicates that the intrac-ortical inhibition as measured by the paired-pulse techniqueat an interstimulus interval of 2 ms was normal in bothcerebral hemispheres. Testing the interhemispheric inhibi-tion, we found that stimulation of neither the left nor theright hemisphere prior to applying the test-stimulus in thecontralateral hemisphere induced a decrease of the evokedMEP for interstimulus intervals of 2, 8 and 10 msec (Fig. 5b).This showed a lack of interhemispheric inhibition.

Discussion

This patient with an infarction of the corpus callosum pre-sented with a bimanual coordination deficit. He was unable toperform complimentary functions with his hands, e.g. turninga page of the newspaper. Moreover, when asked to performdiscrete finger movements with both hands, they were tempo-rally decoupled and would accelerate, particularly in his lefthand. He even failed to perform any type of rhythmic move-ments in concert with his two hands. The deficit was shownby paired-pulse TMS investigations to result from a dis-connnection of the motor cortices in either cerebral hemi-sphere, although both motor cortices were normal in terms ofcorticospinal output magnitude and intracortical inhibition asprobed by single- and paired-pulse TMS, respectively. Sincehis deficit of synergistic movements of both hands becamereadily evident in simple thumb-index oppositions, we usedthe latter as tool for a functional activation study. Most remark-ably, we showed with fMRI that synchronization of the repet-itive thumb-index opposition movements of both hands withvisual pacing was related to an extra activation of a bilaterallateral occipital-premotor-cerebellar circuit. Thus, the visualstimulus seemed to engage two identical networks in eachhemisphere, which allowed the patient to recouple his biman-ual finger movements. This observation was in accordancewith the notion of two classes of bimanual coupling: one isactive at the execution level and is not sensitive to visual cues,

Fig. 3. Electromyographic activity of self-paced and visually paced bimanualthumb-index oppositions in the patient. Note the acceleration of the EMGburst activity during self-paced movements, particularly on the left side. Phasecoupling of finger movements is shown by the correlation of the electromyo-grams recorded from the first dorsal interosseus muscle of either hand duringself-paced and visually paced thumb-index opposition movements. Note thesharp peak of correlation for self-paced and visually paced bimanual move-ments in two healthy controls. In contrast, such a coupling was present in thepatient only during visually paced bimanual movements but not during self-paced bimanual movements. Note the high regularity of the well coordinatedbimanual movements evident from the additional phase coupled correlationpeaks.

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Bimanual coordination deficit 321

while the other is sensitive to an external, visual reference(Weigelt and Cardoso de Oliveira, 2003). Notably, visualrepresentation of bimanual movements can affect not onlycyclic but also discrete movements. In comparison, ourhealthy controls showed a predominant role of the cortex lin-ing the left intraparietal cortex for visually paced bimanualmovements.

Patients with acquired callosal defects, including those whosuffer from callosal infarction due to occlusion of the anterior

cerebral artery, are rare and difficult to diagnose (Kasow et al.,2000; Kumral et al., 2002). As with our patient, they oftensuffer from unspecific cerebrovascular risk factors such asinsulin-dependent diabetes mellitus and arterial hypertensionbut fail to show specific neurological deficits. However,lesions of the frontal midline structures, including the corpuscallosum, have been shown to induce disturbances of biman-ual coordination involving hand and finger movements (Dicket al., 1986; McNabb et al., 1988; Feinberg et al., 1992; Stephanet al., 1999a; Serrien et al., 2000). Moreover, anterior callo-sotomy has been shown to affect movement initiation in rela-tion to self-referential cues, while posterior lesions result inan increase in the variability of simultaneous movementswith reference to external cues (Eliassen et al., 2000).Recently, callosotomy was reported to induce a lack oftemporal coupling during continuous movements while thecoupling of discrete (tapping-like) bimanual movements waspreserved (Kennerley et al., 2002). Force coupling may alsobe impaired after callosotomy (Diedrichsen et al., 2003).Amazingly, patients with acquired callosal defects maysucceed in performing goal-directed bimanual actions likeopening a drawer but tend to desynchronize the activities ofboth hands during circling movements, particularly during

Fig. 4. Abnormal activations bilateral in premotor cortex, presumable visual area V5 and anterior lateral cerebellum as evident from fMRI during thumb-indexopposition movements in the patient (top row). Note the activations in left parietal cortex and right anterior parasagittal cerebellum in the healthy subjects (lowerrow). Shown are the signal increases related to visually paced movements compared with self-paced movements (p < 0.001, corrected).

Table 2. Motor evoked potentials (MEP) in the patient

Muscle Relative Amplitude (%)

Central Latency (ms)

Postexcitatory Inhibition (ms)

FDI L 73 5.2 253FDI R 64 5.4 236TA L 64 15.6 271TA R 52 14.8 273

Amplitude of the MEP after TMS relative to electrical stimulation of thecorresponding peripheral nerve. Central latency calculated as latency of MEPafter TMS minus latency of MEP after magnetic stimulation of correspondingspinal root. FDI: First dorsal interosseus muscle, TA: anterior tibial muscle,R: right, L: left.

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anti-phasic movements (Franz et al., 2000; Serrien et al.,2001). This also holds similarly for patients with callosalinvolvement in multiple sclerosis (Meyer et al., 1995, Larsonet al., 2002; Schmierer et al., 2002). While movement initia-tion is affected in these patients, visual guidance of move-ments allows proper performance of bilateral movementsynergies. In contrast, new bilateral movements cannot belearned by patients with callosal damage (Franz et al., 2000).Our patient was severely impaired during bimanual move-ments even when he attentively tried to guide them by visualcontrol as during knife-fork interactions while eating andwhen turning the pages while reading. It is likely that this def-icit is a result of the damage to both anterior and posteriorparts of his corpus callosum (Fig. 1).

In addition to the infarction involving the entire corpuscallosum from its rostral to its caudal parts, our patient alsoshowed some involvement of the white matter underlying theright anterior cingulate (Fig. 1). This associated lesion of theright anterior cingulate is likely to explain the alien limbphenomenon that the patient experienced initially after theinsult since it is typical for frontomesial brain lesionsthat include the cingulate gyrus (Feinberg et al., 1992). InBrinkman’s study (1984) a lesion of the SMA contralateral tothe preferred hand was shown to result in a performance defi-cit on a visually guided bimanually synergistic task. This per-formance deficit was alleviated by subsequent callosaltranssection (Brinkman, 1984). Bilateral coordination deficitshave also been reported in patients with lesions in thedominant SMA (McNabb et al., 1998; Feinberg et al., 1992).Interpretation of these findings is difficult. In this regard,functional imaging studies have added important insightssince they have shown that during bimanual coordinationtasks, besides activation in the SMA, the cingulate motor area(CMA), premotor cortex, sensorimotor cortex and anteriorcerebellum are also activated (Lang et al., 1990; Stephan et al.,1999b; Ehrsson et al., 2000; Debaere et al., 2001; Tracy et al.,2001; Meyer-Lindenberg et al., 2002). Stephan et al., (1999a)

reported that a bimanual coordination deficit of continuous aswell as discrete movements occurs in patients with a lesion ofthe right middle cingulate, probably including the CMA. Ourpresent patient also had an additional lesion affecting theright anterior cingulate. Given the multiplicity of motor rele-vant areas in the frontal midline cortex (Luppino et al., 1991;Picard and Strick, 1996) and the complex patterns of transcal-losal connectivity (Marconi et al., 2003), we would like tospeculate that both the SMA and the CMA play a critical, butapparently different role in bimanual coordination as suggestedrecently (Seitz et al., 2000). A lesion of the dominant SMAseems to result in a situation where the right CMA interfereswith bimanual coordination, which can be remedied bysubsequent section of the corpus callosum (Brinkman 1984).In contrast, a lesion of either the right cingulate or the corpuscallosum irreversibly deranges the performance of internallygenerated movements that are temporally related to each other(Ringo et al., 1994; Schmierer et al., 2002). The new findingin this study is that bimanual coordination could be restoredby pacing the repetitive bimanual finger movements. Thesefindings are in accordance with earlier observations by Swin-nen et al. (1993) that visual feedback enhances the perfor-mance in tasks requiring bimanual coordination.

The cerebral activity related to the visually paced in-phasemovements of both hands was accompanied by a bilateralactivation in dorsal premotor cortex, lateral occipital cortexand anterior lateral cerebellum in the patient (Fig. 4). Asalso observed in the controls, the additional activation in theright lateral occipital cortex was probably related to increasedvisual attention (Corbetta et al., 1993; Heinze et al., 1994).The activation along the intraparietal sulcus of the dominanthemisphere was probably related to the temporal sequencingof the repetitive movements for both hands (Schwartz andThïer, 1999; Seitz and Binkofski, 2003). In contrast, the lateralpremotor cortex activation in our patient may correspond tosingle neuron recordings in behaving monkeys according towhich the lateral premotor cortex accommodates visually

Fig. 5. a) Normal intracortical inhibition as shown with paired-pulse TMS with an interstimulus interval of 2 ms in the right (square) and left (circle) first dorsalinterosseus muscle. Note the intracortical inhibition also for high intensity of CS. b) Lack of interhemispheric inhibition as tested with paired-pulse TMS for differ-ent interstimulus intervals. The MEPs were not different between the right (square) and left (circle) first dorsal interosseus muscle. Shown are mean +/- standarddeviations.

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Bimanual coordination deficit 323

responsive neurons that mediate the external guidance ofmovements (Kurata and Wise, 1988; Halsband et al., 1994).Further, the enhanced premotor activity may reflect a greaterchallenge for our patient to coordinate bilateral movementssimilar to the greater difficulty of performing parallel thanmirrored finger movements (Sadato et al., 1997). Since in ourpatient both of the two hemispheres were paced visually, thevisual-premotor-cerebellar followed a virtually mirror-likepattern, including the lateral occipital cortex and anterior cer-ebellum. The engagement of this bilateral network supportsthe notion that perception plays an important role in bimanualcoordination (Mechsner et al., 2001; Weigelt and Cardoso deOliveira, 2003). As we will discuss below, the enhanced acti-vation in the cerebellum of our patient may suggest that hissynchronized bimanual activity during visual pacing mayhave resulted from the recoupling of his brain activity byaction of the cerebellum.

The use and control of bimanual movements for goal-directed actions are learned during childhood (Lederman andKlatzky 1987). Interestingly, attentional costs decrease duringthe progress of learning bimanual coordination and, in partic-ular, after excessive training, as in musicians (Temprado et al.,2002; Jäncke et al., 2000b). This may correspond to the findingthat, in a goal-oriented bimanual movement sequence task,the covariation of the two hands was particularly striking whenmonkeys performed the task without vision (Kazennikov et al.,(1994). Thus, kinaesthetic signals appeared to be sufficient tocoordinate the two limbs according to a memorized plan for agoal-directed unitary action. Consequently, there is not onlyspatial but also a tight temporal coupling of the brain activityacross both cerebral hemispheres. In fact, catching an objectwith both hands exhibits strong associations of the peakvelocity of the movements of each hand (Tayler and Davids,1997). In accordance with these behavioral data, electroen-cephalography has revealed that there is an interhemispherictask-related coherence that increases selectively in the earlyphase of bimanual skill acquisition but decreases to levelssimilar to those in unimanual control after training (Andreset al., 1999). Also, a coherence analysis of the beta-band of theelectroencephalogram and paired-pulse TMS studies hasshown that bimanual movements are controlled by the domi-nant hemisphere (Netz et al., 1995; Serrien et al., 2003). Nev-ertheless, interhemispheric coupling is sensitive to a numberof factors, including movement rate. For example, in healthysubjects, anti-phase movements of finger tapping decomposeat lower frequencies than in-phase movements (Forrester andWhitall, 2000). The cortical structures governing this bilat-eral activity have not been well defined as yet. In awake mon-keys, the motor cortex was shown to be of critical importancein bimanual coordination (Donchin et al., 1998). The handrepresentation in motor cortex exhibits a modest callosal pro-jection to motor and premotor cortex but virtually none to theSMA (Rouiller et al., 1994). In contrast, the hand representa-tion in the supplementary motor area has a dense callosal pro-jection to the contralateral SMA, bilateral premotor cortexand cingulate motor area (Rouiller et al., 1994; Liu et al.,

2002). Based on this anatomic information, the SMA seemsparticularly well suited to mediate bilateral interlimb coordi-nation. The interhemispheric conduction takes place in therange of a few milliseconds, mediated by average-sizedmyelinated fibers (Ringo et al., 1994; Schmierer et al., 2002).This tight and multiple interhemispheric connectivity sub-serves bilateral brain activity. In fact, it is also likely to be ofrelevance for cognitive processes. Specifically, verbal fluencyhas been shown to correlate positively with the area of thesplenium of the callosum, while the posterior callosum hasbeen shown to be smaller in subjects with a prominent lan-guage lateralization (Hines et al. 1992).

In our patient, we provided evidence by paired-pulse TMSthat the bimanual coordination deficit resulted from a callosaldisconnection resembling split brain patients (Gazzanigaet al., 1985). This was derived from the lack of interhemi-spheric inhibition in our patient (Fig. 5). Investigations inhealthy subjects using rapid TMS have shown that there is adynamic rivalry between the two cerebral hemispheres(Kobayashi et al., 2003). Specifically, these authors foundthat rTMS shortened the execution time of a motor task withthe ipsilateral hand without affecting performance of thecontralateral hand. This resulted probably from a TMS-inducedrelease from transcallosal inhibition. Nevertheless, a disin-hibition of the motor cortex found in several diseases affect-ing motor performance such as stroke, basal ganglia diseasesor in poststroke focal seizures (Kessler et al., 2002; Bütefischet al., 2003) was absent in our patient. Therefore, our datasuggest that the bimanual coordination deficit evident in ourpatient is probably a result of callosal disconnection of bothcerebral hemispheres rather than from motor cortical disinhi-bition in either cerebral hemisphere. Furthermore, rTMS ofthe anterior SMA has been shown to increase the time lagbetween the onset of the left hand opening a drawer and thestart of the right hand to catch the ball when the ball had to beinserted into the drawer (Obhi et al., 2002). In contrast, therewas no effect of rTMS of the anterior SMA on unimanualtasks. Our patient exhibited some evidence for a leading roleof the left SMA for movement initiation, since in the self-paced task particularly the left hand accelerated to high fingermovement rates. Therefore, the transcallosal connection betweenboth sensory areas was also clearly damaged. Further, sincehe was not able to compensate for his deficient bimanual syn-ergies by visual guidance, the posterior portion of his corpuscallosum was also functionally incompetent, leaving both ofhis hemispheres completely separated. Only external pacingprovided to both hemispheres allowed him to recouple bilat-eral actions. His activation pattern suggests that visual pacingallowed him to synchronize his finger movements in bothhands by using the sensorimotor networks of both cerebralhemispheres. Recently, the cerebellum has been shown to beof particular importance during bimanual activities (Stephanet al., 1999b; Tracy et al., 2001), interlimb and eye-handcoordination (Miall et al., 2000; Ehrsson et al., 2000), tem-poral discrimination and timing of discrete movements(Jueptner et al., 1996; Kawashima et al., 2000; Spencer et al.,

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2003). In view of these findings, it is tempting to speculatethat the activity in both cerebral hemispheres was recoupledby the mediation of subcortical structures, including thelateral cerebellum, allowing for synchronized movements ofboth hands.

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