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Pyramidal tract lesions and movement-associated cortical recruitment in patients with MS

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Pyramidal tract lesions and movement-associated cortical recruitment in patients with MS
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  Pyramidal tract lesions and movement-associated cortical recruitmentin patients with MS Maria A. Rocca, a,b Antonio Gallo, a,b Bruno Colombo,  b Andrea Falini, c Giuseppe Scotti, c Giancarlo Comi,  b and Massimo Filippi a,b, * a   Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Milan, Italy  b  Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy c  Department of Neuroradiology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy Received 23 December 2003; revised 14 April 2004; accepted 4 May 2004 Cortical functional changes, with the potential to limit the functionalconsequences of tissue injury, have been shown in patients with multiplesclerosis (MS). In this study, we assessed the influence of MS-relatedtissue damage of the brain portion of the left pyramidal tract on thecorresponding movement-associated patterns of cortical recruitment inalargesampleofMSpatientswhenperformingasimplemotortaskwiththeir fully normal functioning right upper limbs.We investigated 76 right-handed patients with definite MS. In eachsubject, functional magnetic resonance imaging (fMRI) was acquiredduring the performance of a simple motor task with the dominant, rightupper limb. During the same session, dual-echo, magnetization transfer(MT) and diffusion tensor (DT) MRI sequences were also obtained toquantify the extent and the severity of pyramidal tract damage.Lesions along the left pyramidal tract were identified in 43 patients.Comparedtopatientswithoutpyramidaltractlesions,patientswithsuchlesions had more significant activations of the contralateral primarysensorimotor cortex (SMC), secondary sensorimotor cortex (SII),inferior central sulcus, and cingulate motor area (CMA). They alsoshowed more significant activations of several regions of the ipsilateralhemisphere, including the primary SMC and the precuneus. In thesepatients, T2 lesion load of left pyramidal tract was correlated with theextent of activation of the contralateral primary SMC ( r  2 = 0.25,  P   <0.0001), whereas no correlations were found between the extent of fMRIactivationsandtheseverityofintrinsiclesiondamage,aswellaswithleftpyramidal tract normal-appearing white matter damage.This study shows that, in patients with MS, following injury of themotor pathways, there is an increased recruitment of a widespreadsensorimotor network, which is likely to contribute to limit theappearance of overt clinical deficits. n  2004 Elsevier Inc. All rights reserved.  Keywords:  Multiple sclerosis; Lesion; Cortex Introduction A number of functional magnetic resonance imaging (fMRI)studies have demonstrated that the human brain is capable of adaptive reorganization after central nervous system (CNS) injuryof different nature. The largest amount of data derives fromstudies of the motor system from patients with stroke (Calauttiand Baron, 2003) and multiple sclerosis (MS) (Filippi and Rocca, 2003). Even if these two conditions have different pathogenesisand evolution, all the available data suggest that an alteredrecruitment of the ipsilateral primary sensorimotor cortex(SMC) might influence the recovery of function after an acutelesion affecting the motor system. While the short-term role of the ipsilateral SMC activation on clinical recovery has beenshown by a serial fMRI study of a single patient  (Reddy et al.,2000a), the effect of pyramidal tract damage on the patterns of movement-associated activations has not been fully elucidated yet in MS patients who are clinically stable.In an attempt to support the hypothesis that cortical reor-ganization of specific brain regions may contribute to therecovery or maintenance of function despite the presence of lesions in critical brain sites, we recruited a large sample of MS patients with a preserved function of the dominant, right upper limb and, using fMRI, we assessed the influence, if any,of lesion location along the left pyramidal tract on themovement-associated brain pattern of cortical activations duringthe performance of a simple motor task. Since previous studieshave shown that the severity of intrinsic damage of T2-visiblelesions and normal-appearing white matter (NAWM) can mod-ulate cortical reorganization in MS patients (Filippi and Rocca,2003), we also addressed this issue by measuring the magne-tization transfer ratio (MTR) and diffusivity characteristics of the lesions and NAWM of the pyramidal tract. These measuresmight indirectly reflect pyramidal tract function, as suggested by studies conducted on patients with amyotrophic lateralsclerosis where MTR and diffusivity of the affected cortico-spinal tracts were strongly related to clinical measures of motor neuron dysfunction (Tanabe et al., 1998) and prolongation of  central conduction time (Sach et al., 2004). 1053-8119/$ - see front matter   n  2004 Elsevier Inc. All rights reserved.doi:10.1016/j.neuroimage.2004.05.005* Corresponding author. Neuroimaging Research Unit, Department of  Neurology, Scientific Institute and University Ospedale San Raffaele, ViaOlgettina 60, 20132 Milan, Italy. Fax: +39-2-2643-3031.  E-mail address:  massimo.filippi@hsr.it (M. Filippi). Available online on ScienceDirect (www.sciencedirect.com.) www.elsevier.com/locate/ynimg NeuroImage 23 (2004) 141–147  Patients and methods  Patients We studied 76 consecutive right -handed clinically definiteMS patients (McDonald et al., 2001) (48 women, 28 men, meanage = 45.1 years, range = 21–69 years, median disease duration =9.8 years, range = 1–40 years, median expanded disabilitystatus scale score [EDSS](Kurtzke, 1983) = 2.5, range = 0.0– 6.5). At time MRI was performed, all patients had been relapse-and steroid-free for at least 6 months. Twenty patients have had previous relapses involving the right upper limb. Fifteen right-handed healthy volunteers with no previous history of neuro-logical dysfunction and a normal neurological exam (9 womenand 6 men, mean age = 45.3 years, range = 23–62 years)served as controls. At the time fMRI was acquired, all subjectswere assessed clinically by a single neurologist, who wasunaware of the MRI and fMRI results. Local Ethical Committeeapproval and written informed consent from each subject wereobtained before study initiation.  Functional assessment  Motor function assessment was performed for all the sub- jects at the time of MRI acquisition, using the nine-hole peg-test (9-HPT) and the maximum finger-tapping frequency (Hern-don, 1997). The maximum finger-tapping rate was observed for two 30-s trial periods outside the magnet, and the meanfrequency to the nearest 0.5 Hz entered the analysis. Time tocomplete the 9-HPT and finger tapping rate were similar  between the two groups of  patients and did not differ fromthose of healthy volunteers (Table 1).  Experimental design Using a block design (ABAB), where five periods of activation were alternated with six periods of rest, the subjectswere scanned while performing a simple motor task consistingof repetitive flexion–extension of the last four fingers of thedominant right hand moving together. The movements were paced by a metronome at a 1-Hz frequency. Patients weretrained before performing the study. The subjects wereinstructed to keep their eyes closed during fMRI acquisitionand were monitored visually during scanning to ensure accuratetask performance and to check for additional movements (e.g.,mirror movements).  fMRI acquisition Brain MRI scans were obtained using a 1.5-T machine(Vision, Siemens, Enlargen, Germany). Sagittal T1-weightedimages were acquired to define the anterior–posterior commis-sural (AC–PC) plane. Functional MR images were acquiredusing a T2*-weighted single-shot echo-planar imaging (EPI)sequence (TR = 3.0 s, TE = 66 ms, flip angle [FA] = 90 j ,matrix size = 128    128, field of view [FOV] = 256    256mm). Twenty-four axial slices, parallel to the AC–PC plane,with a thickness of 5 mm, covering the whole brain wereacquired during each measurement. Shimming was performedfor the entire brain using an auto-shim routine, which yieldedsatisfactory magnetic field homogeneity. Structural MRI acquisition Using the same magnet, the following sequences of the brainwere acquired: (a) dual-echo turbo spin echo sequence (TSE)(TR = 3300 ms, first echo TE = 16 ms, second echo TE = 98ms, echo train length = 5); (b) 2D gradient-echo (GE) (TR =640, TE = 12, FA = 20 j ), with and without an off-resonanceradio-frequency (RF) saturation pulse (offset frequency = 1.5kHz, Gaussian envelope duration = 16.4 ms, FA = 500 j ), and(c) pulsed-gradient spin-echo (PGSE) echo-planar sequence(inter-echo spacing = 0.8, TE = 123), with diffusion gradientsapplied in eight non-collinear  directions, chosen t o cover threedimensional space uniformly (Jones et al., 1999). The duration and maximum amplitude of the diffusion gradients were, re-spectively, 25 ms and 21 mTm  1 , giving a maximum b factor in each direction of 1044 s mm  2 . To optimize the measure-ment of diffusion only two b factors were used ( b 1 c 0,  b 2  =1044 s mm  2 ) (Bito et al., 1995). Fat saturation was performed using a four RF pulse binomial pulse train to avoid thechemical shift artefact. A birdcage head coil of approximately300 mm diameter was used for RF transmission and for signalreception. For the TSE and GE scans, 24 contiguous interleavedaxial slices were acquired with 5-mm slice thickness, 256   256 matrix and 250    250 mm 2 FOV. The slices were positioned to run parallel to a line that joins the most infero-anterior and infero-posterior parts of the corpus callosum (Miller et al., 1991). For the PGSE scans, ten axial slices with 5-mmslice thickness, 128    128 matrix and 250    250 mm 2 FOVwere acquired, with the same orientation as the dual echo scans,with the second-last caudal slice positioned to match exactly thecentral slices of the dual-echo and GE sets. This brain portionwas chosen since the periventricular area is a common locationfor MS lesions. In addition, these central slices are less affected by the distortions due to B 0  field inhomogeneity, which canaffect image co-registration.  fMRI analysis All image post-processing was performed on an independent computer workstation (Sun Sparcstation, Sun Microsystems,Mountain View, CA). fMRI data were analyzed using thestatistical parametric mapping (SPM99) software (Friston et al.,1995). Before statistical analysis, all images were realigned tothe first one to correct for subject motion, spatially normalizedinto the standard space of SPM, and smoothed with a 10-mm,3D-Gaussian filter. Table 1Functional assessment of right upper limbs healthy volunteers and MS patients with and without T2 lesions along the left pyramidal tract HealthyvolunteersLesion + Lesion   Mean time to completethe nine-hole peg test (SD) [s]19.8 (3.2) 20.6 (3.3) 20.8 (3.0)Mean maximum finger tapping rate (SD) [/s]3.6 (0.4) 3.5 (0.5) 3.3 (0.5)MS = multiple sclerosis; SD = standard deviation; Lesion + = presence of T2 lesions along the left pyramidal tract; Lesion  = no T2-visible lesionsalong the left pyramidal tract.See text for further details.  M.A. Rocca et al. / NeuroImage 23 (2004) 141–147  142  Structural MRI post-processing  Lesions located along the left pyramidal tract, from cortexto brainstem, were identified by one experienced observer unaware of the fMRI results, on the proton-density weightedimages. The corresponding T2-weighted images were alwaysused to increase confidence in lesion identification. Then, left  pyramidal tract lesion volumes were measured using a seg-mentation technique based on local thresholding, as previouslydescribed (Filippi et al., 2001). After co-registration of the two GE scans using a surface-matching technique based on mutualinformation (Studholme et al., 1996), MTR  images were derived pixel-by-pixel (Filippi et al., 1999). Extra-cerebral tissue was removed from MTR ma ps using the same tech-nique used for lesion segmentation (Filippi et al., 2001), and the resulting images were co-registered with the T2-weightedimages (Studholme et al., 1996). PGSE images were first  corrected for distortion induced by eddy currents using analgorithm which maximizes mutual information between thediffusion un-weighted and weighted images (Studholme et al.,1996). Then, the diffusion tensor was calculated, and meandiffusivity (MD) and fractional anisotropy (FA) derived for every pixel, as previously described (Filippi et al., 2001). The diffusion images were interpolated to the same image matrixsize as the dual-echo, and then the  b  = 0 step of the PGSEscans (T2-weighted, but not diffusion weighted) were co-registered with the dual-echo T2-weighted images using athree-dimensional rigid-body co-registration algor ithm basedon mutual information (Studholme et al., 1996). The final step consisted of automatic transfer of pyramidal tract lesionoutlines onto the MTR, MD, and FA maps to calculateaverage lesion MTR, MD, and FA. Using square regions of interest (ROIs) of 8.6 mm 2 , MTR, MD, and FA values of  NAWM were also calculated along the left pyramidal tract inareas that appeared normal on T2-weighted scans. Statistical analysis Changes in blood oxygenation level dependent (BOLD)contrast associated with the performance of the motor task wereassessed on a pixel-by-pixel basis, using the general linear model (Friston et al., 1995) and the theory of Gaussian fields(Worsley and Friston, 1995). Specific effects were tested byapplying appropriate linear contrasts. Significant hemodynamicchanges for each contrast were assessed using t statistical parametric maps (SPMt). The intra-group activations and com- parisons between groups were investigated using a random-effect analysis (Friston et al., 1999), with a one-sample or  two-sample  t   test performed as appropriate. Within-group acti-vations were tested at a threshold of   P   < 0.05, corrected for multiple comparisons. For between-group comparisons, cluster of voxels with a height threshold  P   < 0.001 (uncorrected) andan extent threshold  P   < 0.05 (corrected) were considered assignificant.To assess the correlation of BOLD changes with clinical dataand quantities derived from brain MRI, these metrics wereentered into the SPM design matrix, using basic models andlinear regression analysis (Friston et al., 1999). Cluster of  voxels with a height threshold  P   < 0.001 (uncorrected) andan extent threshold  P   < 0.05 (corrected), were considered assignificant. Results Conventional MRI  Lesions along t he left pyramidal tract were identified in 43 patients. In Table 2, the main demographic and clinical character- istics of patients with and without such lesions are shown. Themedian T2-weighted load of lesions of the left pyramidal tract was0.26 ml (range = 0.04–2.4 ml), average lesion MTR 40.0% (SD =2.9%), average lesion MD 0.85    10  3 mm 2 s  1 (SD = 0.08   10  3 mm 2 s  1 ), and average lesion FA 0.36 (SD = 0.01). Thesevalues were significantly different from those obtained from ROIsof NAWM measured in the same left pyramidal tract (MTR  NAWM = 43.2%,  P   = 0.0001; MD NAWM = 0.76    10  3 mm 2 s  1 ,  P   = 0.0001; FA NAWM = 0.54,  P   = 0.0001).  Functional MRI  During fMRI acquisition, all subjects performed the task correctly and no additional movements were noted. All subjectsshowed a brain pattern of cortical activations, which is knownto be associated with motor planning and performance (Fink et al., 1997) and which typically involves cortical and subcor- tical areas (Table 3).  Patients with pyramidal lesions vs. healthy volunteers Compared to healthy volunteers, patients with pyramidaltract lesions had more significant activations of the primarysensorimotor cortex (SMC), bilaterally, (SPM space coordinates:  54,   18, 44 and 42,   14, 56;  z   values = 3.41 and 4.56), thecingulate motor area (CMA), bilaterally (SPM space coordi-nates: 0,   16, 38;  z   value = 3.65), the contralateral secondarysensorimotor cortex (SII) (SPM space coordinates:   62,   32,14;  z   value = 3.15), the contralateral supplementary motor area(SMA) (SPM space coordinates:   4,   10, 58;  z   value = 3.35),and the ipsilateral intraparietal sulcus (IPS) (SPM space coor-dinates: 30,   58, 54;  z   value = 3.11).  Patients without pyramidal lesions vs. healthy volunteers Compared to healthy volunteers, patients without pyramidaltract lesions had more significant activations of the ipsilateralCMA (SPM space coordinates: 2,   10, 36;  z   value = 3.51), theIPS, bilaterally (SPM space coordinates:   28,   72, 34 and 32,  62, 56;  z   values = 4.67 and 3.62) and the contralateral thalamus(SPM space coordinates:   22,   22, 18;  z   value = 3.33). Table 2Main demographic and clinical characteristics of MS patients with andwithout T2 lesions along the left pyramidal tract  Number of subjects(M/F)Mean age(range)Median EDSSscore (range)Median diseaseduration (years)(range)Lesion + 43 (13/30) 45.0 (24–64) 3.0 (0.0–6.5) 9 (1–40)Lesion    33 (15/18) 45.2 (21–68) 2.5 (0.0–7.5) 10 (1–33)M = male; F = female; EDSS = Expanded Disability Status Scale;Lesion + = presence of lesions along the left pyramidal tract; Lesion    =no T2-visible lesions along the left pyramidal tract.  M.A. Rocca et al. / NeuroImage 23 (2004) 141–147   143   Patients with pyramidal tract lesions vs. patients without  pyramidal tract lesions Compared to patients without pyramidal lesions, patients withsuch lesions had more significant activations of the contralateral primary SMC (SPM space coordinates:   46,   8, 46 and   30,  22, 50;  z   values = 4.18 and 4.34), SII (SPM space coordinates:  52,  34, 20;  z   value = 3.86), inferior central sulcus (SPM spacecoordinates:   60, 2, 12;  z   value = 2.94), and CMA (SPM spacecoordinates:  8, 40, 10;  z   values = 4.09). They also showed moresignificant activations of several regions of the ipsilateral hemi-sphere, including the primary SMC (SPM space coordinates: 36,  22, 44 and 46,   20, 58;  z   values = 3.44 and 3.03) and the precuneus (SPM space coordinates: 12,  68, 48 and 16,  54, 46;  z   values = 4.19 and 3.92) (Fig. 1).Compared to patients with pyramidal lesions, those without such lesions had more significant activations of the contralateralthalamus (SPM space coordinates:  10,  14,  2;  z   value = 2.94),IPS (SPM space coordinates:  28,  70, 34;  z   values = 3.82), andIFG (SPM space coordinates:   42, 4, 32;  z   value = 3.69). They Fig. 1. Relative cortical activations of MS patients with lesions in the left pyramidal tract during the performance of a simple motor task with their clinicallyunimpaired, fully normal functioning and dominant right hands (two-sample  t   test, height threshold  P   < 0.001[uncorrected], extent threshold  P   < 0.05[corrected]). Compared to MS patients without pyramidal tract lesions, they showed increased recruitment of the ipsilateral primary sensorimotor cortex (A, B), precuneus (B, F) and of the contralateral primary sensorimotor cortex (B), inferior central sulcus (C, E), secondary somatomotor cortex (C) and cingulate motor area (C–E).Table 3Activation sites in healthy subjects and MS patients (with and without lesions in the left pyramidal tract) during task performance (random-effect analysis,within-group one-sample  t   test,  P   < 0.05 corrected for multiple comparisons)Activation site Healthy subjects Lesion + Lesion   SPM space coordinates  X Y Z  Z   score SPM space coordinates  X Y Z  Z   score SPM space coordinate  X Y Z  Z   scoreR cerebellum 20,   44,   24 6.63 28,   48,   32 7.81 24,   56,   22 6.74L thalamus   8,   16, 6 4.38   14,   20, 2 5.75   12,   18, 4 7.36L SII   58,   22, 18 5.04   50,   26, 16 6.48   58,   30, 20 6.21L CMA   6,   8, 48 4.33   6, 8, 36 7.20   6,   4, 46 6.91L SMC   36,   24, 56 6.32   38,   22, 60 inf.   38,   28, 56 inf.R SMC 56,   34, 52 4.19 42,   40, 60 6.71 50,   36, 50 6.20Bilateral SMA 0, 2, 44 5.30 0,   4, 54 inf. 0,   10, 62 6.62L Rolandic operculum – –    56, 6,   2 6.49 – – L IFG   56, 4, 28 4.51   58, 4, 28 4.46   54, 4, 28 5.65R MFG – – – – 36,   8, 58 4.65Lesion + = presence of lesions along the left pyramidal tract; Lesion    = no T2-visible lesions along the left pyramidal tract; SII = secondary sensorimotor cortex; CMA = cingulate motor area; SMC = primary sensorimotor cortex; SMA = supplementary motor area; IFG = inferior frontal gyrus; MFG = middlefrontal gyrus; L = left; R = right. See text for further details.  M.A. Rocca et al. / NeuroImage 23 (2004) 141–147  144  also showed a more significant activation of the ipsilateral MFG(SPM space coordinates: 42, 36, 22, and 2, 20, 48;  z   values = 3.31and 3.51).In patients with pyramidal lesions, T2 lesion load of the left  pyramidal tract was correlated with the extent of activation of thecontralateral primary SMC (SPM space coordinates:  28,  24, 56; r  2 = 0.25,  P   < 0.0001) (Fig. 2). No other clusters showed a significant correlation with T2 lesion load of the left pyramidaltract. No correlation was found between the extent of fMRIactivations and average MTR, MD, and FA of lesions and NAWMROIs of the left pyramidal tract. Discussion Recently, several fMRI studies investigated the movement-associated cortical pattern of activations in patients with MS andhave suggested that cortical reorganization is likely to contributeto the maintenance of a normal level of function in the presenceof widespread brain and cord damage (Filippi and Rocca, 2003;Filippi et al., 2002a,b; Reddy et al., 2000a,b; Rocca et al.,2002a,b, 2003a,b,c). However, the majority of the fMRI studiesof MS have not addressed the potential influence of tissuedamage of critical sites (e.g., the pyramidal tract in case of movement-associated activations) on the pattern of cortical re-cruitment. At present, only two preliminary studies have assessedthe contribution of pyramidal tract lesions on the movement-associated patterns of cortical activations (Pantano et al., 2002;Reddy et al., 2000a) in patients with MS. The first  (Reddy et al.,2000a) is a case report that showed dynamic changes in therecruitment of the ipsi- and contra-lateral primary SMC, whichwere, in turn, associated to the recovery of function and to therestoration of normal N-acet ilaspartate (NAA) levels. The secondstudy (Pantano et al., 2002) assessed 20 patients with a previousclinically isolated syndrome suggestive of MS and showed that the extent of cortical reorganization was greater in patients with a previous hemiparesis and a higher lesion volume along the pyramidal tracts than in those with a previous optic neuritisand no clinical evidence of damage to the pyramidal tracts. Inthe former group, cortical reorganization also involved theipsilateral hemisphere extensively. Whereas both these studiessuggested that lesions in the pyramidal tract can influence the pattern of movement-associated activations, they did not addresswhether such changes might have an adaptive role in limiting thefunctional consequences of MS injury. In addition, they did not investigate whether NAWM damage of the pyramidal tract or theseverity of intrinsic damage of T2-visible lesions also influencefMRI changes.This study, which is the first conducted on a large sample of MS patients representative of the general MS population, dem-onstrates that, in clinically stable patients with MS, the move-ment-associated brain pattern of cortical activations is influenced by the presence of pyramidal tract lesions. When compared tohealthy volunteers and to patients without pyramidal tract lesions,those with such lesions showed a more significant activation of the ipsilateral primary SMC. Since all our patients had no overt clinical involvement of the right upper limb, this finding supportsthe notion that the activation of the ipsilateral hemisphere might contribute to the recovery of function following injury of themotor pathways. This mechanism is not limited to patients withMS (Reddy et al., 2000a), but it rather seems to be o perative in many other neurological conditions, including stroke (Cao et al.,1998; Chollet and Weiller, 1994; Weiller  et al., 1993), congenital hemiplegia (Vandermeeren et al., 2003), and tumors (Yoshiura et al., 1997). Since ipsilateral motor pathways seem to contributeto the control of hand movements in the normal adult  (Boecker et al., 1994; Cramer et al., 1999; Kim et al., 1993; Singh et al.,1998; ) and since they seem to be more extensively recruited withincreased motor task complexity (Ehrsson et al., 2000; Wexler et al., 1997), ipsilateral SMC activation might be viewed as arather common compensatory mechanism, following brain injury,with the potential to facilitate motor unit recruitment. Thishyperexcitability of the unaffected motor cortex might in turn be secondary to an altered transcallosal inhibition, as suggested by studies on stroke (Boroojerdi et al., 1996; Liepert et al., 2000;Traversa et al., 1998). The compensatory role of an increasedcortical recruitment also fits with the previous observation that the correlation between the corticospinal tract lesion burden andthe severity of the corresponding motor impairment is only weak (Riahi et al., 1998).Several studies of patients with MS found a strong relation-ship between the extent of fMRI activations and MRI measuresof structural brain damage, not only within lesions but also in the NAWM (Filippi et al., 2002b; Rocca et al., 2002a,b, 2003a,b,c).In this study, we quantified the severity of tissue damage of lesions and NAWM in the left pyramidal tract and found that theonly variable weakly related to the activity of a given functionalarea (the contralateral primary SMC) was the T2 lesion load of left pyramidal tract, whereas average MTR, MD, and FA of theselesions, as well as those of the NAWM, which are measures of the severity of damage, were not correlated with any fMRImetrics. This rather unexpected finding suggests that, once a Fig. 2. Correlation between relative activation of the contralateral primarysensorimotor cortex (SPM space coordinate:   28,   24, 56) and left  pyramidal tract T2 lesion load in MS patients with such lesions (secondlevel simple regression/correlation analysis). This correlation remainedsignificant even after removing the two ‘‘outliers’’ ( r  2 = 0.24;  P   < 0.001).See text for further details.  M.A. Rocca et al. / NeuroImage 23 (2004) 141–147   145
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