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Cortical Plasticity in Amyotrophic Lateral Sclerosis: Motor Imagery and Function

Background. Cortical networks underlying motor imagery are functionally close to motor performance networks and can be activated by patients with severe motor disabilities. Objective. The aim of the study was to examine the longitudinal effect of
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Documenttranscript Repair Neurorehabilitation and Neural DOI: 10.1177/1545968307300698 2007; 21; 518 srcinally published online May 2, 2007; Neurorehabil Neural Repair  Dorothée Lulé, Volker Diekmann, Jan Kassubek, Anja Kurt, Niels Birbaumer, Albert C. Ludolph and Eduard Kraft Cortical Plasticity in Amyotrophic Lateral Sclerosis: Motor Imagery and Function   The online version of this article can be found at:   Published by:   On behalf of:   American Society of Neurorehabilitation   can be found at: Neurorehabilitation and Neural Repair Additional services and information for Email Alerts: Subscriptions: Reprints: Permissions: Journals Online and HighWire Press platforms): (this article cites 37 articles hosted on the Citations    © 2007 American Society of Neurorehabilitation. All rights reserved. Not for commercial use or unauthorized distribution.  at Bayerische Staatsbibliothek on October 21, 2007 http://nnr.sagepub.comDownloaded from  518 Copyright © 2007 The American Society ofNeurorehabilitation Cortical Plasticity in Amyotrophic Lateral Sclerosis:Motor Imagery and Function Dorothée Lulé,PhD,Volker Diekmann,PhD,Jan Kassubek,MD,Anja Kurt,MD,Niels Birbaumer,PhD,Albert C.Ludolph,MD,and Eduard Kraft,MD Background  .Cortical networks underlying motor imagery arefunctionally close to motor performance networks and can beactivated by patients with severe motor disabilities. Objective  .The aim ofthe study was to examine the longitudinal effect of progressive motoneuron degeneration on cortical representa-tion ofmotor imagery and function in amyotrophic lateralsclerosis. Methods  .The authors studied 14 amyotrophic lateralsclerosis patients and 15 healthy controls and a subgroup of11patients and 14 controls after 6 months with a grip force par-adigm comprising imagery and execution tasks using func-tional magnetic resonance imaging. Results  .Motor imagery activated similar neural networks as motor execution in amy-otrophic lateral sclerosis patients and healthy subjects in theprimary motor (BA 4),premotor,and supplementary motor(BA 6) cortex.Amyotrophic lateral sclerosis patients presenteda stronger response within premotor and primary motor areasfor imagery and execution compared to controls.After 6months,these differences persisted with additional activity inthe precentral gyrus in patients as well as in a frontoparietalnetwork for motor imagery,in which activity increased withimpairment. Conclusion  .The findings suggest an ongoing com-pensatory process within the higher order motor-processingsystem ofamyotrophic lateral sclerosis patients,probably toovercome loss offunction in primary motor and motorimagery-specific networks.The increased activity in precen-tral and frontoparietal networks in motor imagery might beused to control brain-computer interfaces to drive communi-cation and limb prosthetic devices in patients with loss of motor control such as severely disabled amyotrophic lateralsclerosis patients in a locked-in-like state.Key Words: Amyotrophic lateral sclerosis (ALS)—Cortical  plasticity—Motor imagery—fMRI—Brain-computer interfaces. A myotrophic lateral sclerosis (ALS) is a progres-sive neurodegenerative disorder that presentswith a selective but not well-understood patternofthe degeneration ofmotoneurons.Studying neuralcompensatory activity in a progressive disorder such asALS is an important step to understand basic mecha-nisms underlying recovery and plasticity ofthe corticalmotor cortex.The brain has the capacity to change the architectureofthe neural networks during learning or as a responseto injury. 1 Compensatory changes in cortical motorareas have been previously confirmed in ALS with func-tional imaging:different studies reported changes in thepattern ofactivity within the cortical motor network inALS, 2 with an expansion ofactivity into anterior regionscomprising the premotor cortex (PMC). 3-5 Recently,Schoenfeld and his colleagues 6 reported increases ofacti-vation in the ipsilateral motor area as well as difficulty-related activity in the contralateral cerebellar lobe in ALSin a motor task.In addition,an enhanced activity in ALSpatients in a motor task was evident in the supplemen-tary motor area (SMA), 4,5,7 as well as in the contralateral 2 and bilateral 4 sensorimotor cortex encompassing the facearea ofthe contralateral sensorimotor cortex. 3,4 It is sug-gested that marked increase in cortical activation beyondthe primary motor cortex is associated with the degree of upper motor neuron involvement (UNM). 2,4 In addition,enhanced subcortical involvement hasbeen suggested for ALS patients for motor performanceencompassing areas involved in motor learning such asthe basal ganglia,brainstem,and cerebellum. 7 There isevidence that the enhanced recruitment ofanterior cin-gulate regions and the caudate nucleus varies with thedegree ofupper motor neuron involvement. 8 AlthoughBrooks et al 2 reported an increase in the volume acti-vated in ALS patients for imagined movements,the pre-sent study is the first to systematically investigate motorplasticity in ALS for motor imagery in a longitudinal From the Section ofNeurophysiology (DL,VD) and the DepartmentofNeurology (JK,AK,ACL,EK),University ofUlm,Ulm,Germany;Eberhard-Karls-University ofTübingen,Institute ofMedicalPsychology and Behavioral Neurobiology,Germany (DL,NB);and theNational Institutes ofHealth,NINDS,Human Cortical Physiology,Bethesda,Maryland (NB).Address correspondence to Dorothée Lulé,Neurologische Universitäts-klinik Ulm,Sektion Neurophysiologie,Albert-Einstein-Allee 47,é D,Diekmann V,Kassubek J,et al.Cortical plasticity in amy-otrophic lateral sclerosis:motor imagery and function. Neurorehabil Neural Repair  .2007;21:518-526.DOI:10.1177/1545968307300698    © 2007 American Society of Neurorehabilitation. All rights reserved. Not for commercial use or unauthorized distribution.  at Bayerische Staatsbibliothek on October 21, 2007 http://nnr.sagepub.comDownloaded from  design.Accordingly,this is the first study to investigatethe consequences ofprogressive neural loss on motorrepresentation without voluntary movement.Numerous studies 9-13 have verified that executionand imagery ofmovements share some cortical repre-sentations within the motor network,including theprimary motor cortex (M1),PMC,and SMA.In addi-tion,areas engaged in inhibition ofmovement execu-tion are active during imagery.It has been validated in other neurodegenerative dis-eases and in paraparetic patients that networks involvedin motor imagery are similarly affected by reorganiza-tion processes as areas active during motor execution(eg,patients with Parkinson’s disease exhibit reducedactivity both for motor imagery and for execution). 14-16 Motor imagery offers some advantages for studying themotor system with functional magnetic resonanceimaging (fMRI) because behavioral differences inpatients with movement disorders such as ALS do notaffect the ability to perform the task.Besides its relevance for understanding the compen-satory capacity ofthe motor network,motor imagery bears the potential to retain movement execution andcommunication in patients with loss ofcontrol ofthemotor system such as severely disabled ALS patients ina locked-in-like state:with motor imagery,ALS patientsare able to control brain-computer interfaces (BCI) todrive communication and limb prosthetic devices. 17 METHODSPatients and Controls Fourteen ALS patients participated in the study (2women and 12 men;mean age 53 years;range,36-69 years).Amyotrophic lateral scerlosis was diagnosedaccording to the revised El Escorial criteria, 18 all patientspresented the sporadic form ofALS with a spinal onset,and none exhibited major bulbar symptoms.The meanduration ofthe disease was 40 ± 26 months,determinedby the onset ofmotor symptoms.Mean clinical severity ofALS,measured by the ALS functional rating scale(ALS-FRS),was 33.5 ± 8.7 (range,18-41).Five patientsneeded support to walk,and 4 more had difficultieswith walking;1 ofthe former was intermittently venti-lated by noninvasive positive-pressure ventilation at thetime ofthe study.Fifteen age-matched healthy volunteers (5 womenand 10 men;mean age 55;range,37-72) served as con-trols.None ofthe participants had a history ofneuro-logic or psychiatric disorders,all were free ofmedication,and none hit the exclusion criteria ofour study (clinically relevantdepression/majorcognitivedeficitspartici-pantswere characterized neuropsychologicallyfollowingidentical methods,as described earlier). 19 They wereright-handed,as assessed by the Edinburgh Inventory. 20 A subgroup of11 patients and 14 healthy controlswas measured a second time after halfa year (191 ± 15days and 189 ± 8 days,respectively).By then,mean clin-ical severity ofALS,measured by the ALS-FRS,was 28.6 ± 8.9 (range,14-40).Three patients needed a wheel-chair,4 more needed support to walk,and 1 more haddifficulties with walking;the 4 patients with a wheel-chair and 1 ofthose who needed support to walk were intermittently ventilated by noninvasive positive-pressure ventilation at this time ofthe study.The study was approved by the ethics committee of the University ofUlm.All subjects and patients gavewritten informed consent for the study. Experimental Design Each person performed 2 different tasks:the execution of a grip force task and imagery ofthe same movement.During the movement task,subjects had to squeeze a push-button with a defined maximum compressive force of5 Nand about 0.5 cm amplitude.During the imagery task,thesubjects had to imagine the same movement without any muscle activity.The tasks were to be performed at a fre-quency of1 Hz with the right,left,or with both hands,resulting in 6 different tasks (“move left/right/both,”in thefollowing called Ml/Mr/Mb;“imagine left/right/both,”in thefollowing called Il/Ir/Ib) in blocks of28.2 s (equally 10 echoplanar imaging [EPI] scans).Each task block was performed3 times in total,interleaved by rest periods.The tasks wereperformed in a pseudorandomized sequence.Instructionsand the pacing signal were presented via headphones.Before actual magnetic resonance imaging (MRI)scanning,the task was trained in an MRI dummy (lyingposition,MRI scanning noise) with control ofhandmuscle activity until the subjective rating ofimagery intensity reached at least 4 on a scale of0 to 6. Behavioral Recording During execution ofmovements,the number of push-button presses,the velocity ofpressing,the peak amplitude force ofcompression,and the delay betweenpacing signal and push-button press were recordedusing an in-house software tool. fMRI Procedures Images were acquired on a 1.5 T scanner (Symphony,Siemens Medical Systems AG,Erlangen,Germany) withPlasticity in the Motor System in ALSNeurorehabilitation and Neural Repair 21(6);2007  519    © 2007 American Society of Neurorehabilitation. All rights reserved. Not for commercial use or unauthorized distribution.  at Bayerische Staatsbibliothek on October 21, 2007 http://nnr.sagepub.comDownloaded from  a standard head coil.Functional data were obtainedusing gradient-EPI sequences sensitive to the blood oxy-gen level–dependent (BOLD) contrast (3.5-mm slicethickness,0.5-mm gap,3.59 × 3.59 mm 2 in plane reso-lution,64 × 64 × 32 voxels,TE = 50 ms,TR = 2.82 s,flipangle = 90 ° ,32 slices per scan oriented along theanterior-posterior commissure with axial slice orienta-tion).Ten EPI scans were generated for each task andrest period,lasting 28.2 seconds.Three runs of135scans (6.35 minutes each) were measured with 6 task blocks and 7 rest periods per run.The first 5 scans of each run were discarded.T1-weighted anatomical imageswere collected using a high-resolution 3-D sequence(TE/TR/ flip angle = 3.9 ms/1740 ms/15 ° with a voxel sizeof0.9 × 0.9 × 0.9 mm 3 ,256 × 256 × 192 voxels). Image Analysis Image processing was performed using SPM2(Statistical Parameter Mapping software package). 21 Functional data were spatiallyrealigned,coregisteredwith the anatomical scans,and transformed into stereotac-tic space using standard anatomical Montreal NeurologicalInstitute (MNI) space.They were resampled to a 3-mmisometric voxel size and spatially smoothed with anisotropic Gaussian kernel (10 mm full width at half maximum).For brain section labeling,the images weretransferred into Talairach space. 22 Statistical Analysis A general linear model was used in a categorical block design.Tasks were compared to the resting state with aleast squares analysis for the underlying boxcar functionconvolved with a model hemodynamic response function.To suppress slow fluctuations ofthe BOLD signal,thevoxel intensity time series were high-pass filtered (timeconstant 141 seconds),and to compensate for serial cor-relation between successive scans,the noise component inthe model is described by a first-order autoregressivemodel.In addition,regressors for displacement and rota-tion were estimated for each subject and session.For each subject and session,the regressors task minus rest were used as contrasts.These contrasts werethen combined in a second-level analysis (randomeffects) using a mixed model (between-subject factorgroup and within-subject factor condition Ml,Mr,Mb,Il,Ir,Ib) in a 1-way analysis ofvariance (ANOVA) forthe first and second measurements.Because the patientnumber decreased from initial to second measurement,a direct comparison from first to second measurementswas discarded.Based on the results ofthis second stage analysis,thespatial relationship between voxels was used to computebetween-voxel variances as prior distribution varianceparameters for a parametric empirical Bayesian analysisassuming Gaussian prior distributions (for methods,see the work ofFriston and coworkers 23-25 ).The poste-rior distributions ofactivity for each voxel were thenused to make statistical inferences about the probability that an effect exceeded some specified level.The BOLDeffects are assumed to be substantial ifa cluster containsmore than 4 voxels ( ≥ 108 mm 3 ) and ifthe conditionalmean contrast parameters indicate an effect size of more than 1.0 (for movement tasks) or 0.2 (for cogni-tive effects ofimagined movements) in units ofper-centage global mean value with probabilities greaterthan 95%.For the identification ofthe anatomical areas,standard tools were used. 26-29 Correlation analysis for each condition with func-tional impairments in ALS patients,measured by ALS-FRS,was performed using the second-level analysis of simple regression implemented in SPM2.For the behav-ioral recordings,single-subject mean values were gener-ated for each task and compared to controls using anonparametric Mann-Whitney U  test.Due to the smallnumber ofparticipants,all tests were conducted in anexplorative manner,and thresholds were not adjustedfor multiple testing. RESULTSBehavioral Data Patients presented a significant lower mean perfor-mance of75% (percentage ofcorrect movements) thancontrols (96%).Peak amplitude offorce was not signif-icantly different between both groups (ALS patients:4.3N,controls:4.98 N,maximum 5 N).After 6 months,the patients’performance ofcorrectmovements had decreased to 56%,whereas controlsrevealed a consistent performance rate (94%).Therewas a significant decrease in peak amplitude offorce inpatients to 3.4 N but not in controls (4.97 N). fMRI,Motor Execution:DifferencesBetween Groups,First Measurement During right-hand movements,ALS patients exhib-ited a significantly higher BOLD response compared tocontrols in the left-sided PMC (BA 6;6 voxels,2.3% sig-nal change).For movement ofleft and ofboth hands,no significant difference between the groups becameevident.Healthy controls presented no larger BOLDresponse in any area compared to ALS patients.Lulé et al 520 Neurorehabilitation and Neural Repair 21(6);2007    © 2007 American Society of Neurorehabilitation. All rights reserved. Not for commercial use or unauthorized distribution.  at Bayerische Staatsbibliothek on October 21, 2007 http://nnr.sagepub.comDownloaded from  Plasticity in the Motor System in ALSNeurorehabilitation and Neural Repair 21(6);2007  521 fMRI,Motor Imagery:Differences BetweenGroups,First Measurement During imagery ofright-hand movements,ALSpatients exhibited a stronger BOLD response than con-trols in the PMC bihemispherically (BA 6).Duringimagery ofright and both hands movements,the con-trol group displayed a significantly higher BOLDresponse than ALS patients in the right and left superiortemporal gyrus (BA 38),respectively,and for theimagery ofmovements ofboth hands,the activationextended left-sided to BA 21,22,and 42 and right-sidedto BA 22,insula (BA 13),and amygdala (Table 1).Forimagery ofright-hand movements,controls presented ahigher response also in the ipsilateral precuneus (BA 7)and angular gyrus (BA 39).During movement imagery ofleft and ofboth hands,the control group displayed ahigher response than ALS patients in the right-sidedand left-sided medial cingulum (BA 24,32),respec-tively,and in the right-sided putamen (for both hands,see Figure 1).For the imagery ofleft-hand movements,controls also presented an increased BOLD response inthe left-sided caudate body compared to patients. fMRI,Motor Execution:DifferencesBetween Groups,Second Measurement In the second measurement after 6 months,formovement ofthe right and left hands,no significantdifference between the groups became evident.Duringmovement ofboth hands,ALS patients revealed a sig-nificantly higher BOLD response compared to con-trols in the left-sided M1 (BA 4),in the middle andinferior frontal gyrus (BA 9,44,45),and in the inferiorfrontal operculum (Table 2).In addition,ALS patientspresented an increase ofthe BOLD response comparedto controls in the inferior parietal gyrus (BA 40) inboth hemispheres.A larger BOLD response was notobserved in any area for the controls compared to ALSpatients. Table 1. Brain Areas Where ALS Patients Displayed a Significantly Higher Response Than Controls (ALS Patients MinusHealthy Controls) and Controls Displayed a Significantly Higher Response Than Patients (Healthy Controls MinusALS Patients) for Imagery ofHand Movements,Respectively ALS Patients Group Higher BOLD Response Than ControlsMNI Coordinates,mmExperimentalCluster SizeAnatomic AreasSignalCondition(Voxel)(Brodmann Area) XYZ  Change,%Ir26Right precentral/middle frontal gyrus (BA 6)33–6480.325Left superior/middle frontal gyrus (BA 6)–183600.310Left precentral gyrus (BA 6)–45–3510.2Il6Left superior frontal gyrus (BA 8)–1248450.35Right postcentral gyrus (BA 4)48–21360.2IbControl Group Higher BOLD Response Than ALS PatientsIr7Right superior/middle temporal gyrus (BA 38)456–270.311Right precuneus (BA 7)12–54390.29Right angular gyrus (BA 39)48–75360.3Il5Right middle cingulum (BA 32)1221330.25Right middle cingulum (BA 24)3–3300.26Left caudate body–129180.325Right putamen27900.3Ib104Right putamen,insula,superior temporal gyrus,33–3–120.4Heschl gyrus,amygdala (BA 13,22)68Left superior temporal gyrus (BA 21,22,38) –519–90.525Left anterior/middle cingulum (BA 24,32)–918300.48Left superior temporal gyrus (BA 22,42)–60–1230.2Voxels with an effect size ofmore than 0.2% ofglobal mean value for cognitive effects with 95% probabilities are shown.ALS,amyotrophic lateral sclerosis;Ir/Il/Ib,movement imagery ofthe right/left/both hand(s);BA,Brodmann area;BOLD,bloodoxygen level dependent;MNI,Montreal Neurological Institute.    © 2007 American Society of Neurorehabilitation. All rights reserved. Not for commercial use or unauthorized distribution.  at Bayerische Staatsbibliothek on October 21, 2007 http://nnr.sagepub.comDownloaded from
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