A functional MRI study of cortical activations associated with object manipulation in patients with MS

www.elsevier.com/locate/ynimg NeuroImage 21 (2004) 1147 – 1154

A functional MRI study of cortical activations associated with object manipulation in patients with MS Massimo Filippi, a,* Maria A. Rocca, a Domenico M. Mezzapesa, a Andrea Falini, b Bruno Colombo, c Giuseppe Scotti, b and Giancarlo Comi c a

Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, 20132 Milan, Italy Department of Neuroradiology, Scientific Institute and University Ospedale San Raffaele, 20132 Milan, Italy c Department of Neurology, Scientific Institute and University Ospedale San Raffaele, 20132 Milan, Italy b

Received 9 September 2003; revised 8 October 2003; accepted 8 October 2003

Previous functional magnetic resonance imaging (fMRI) studies of simple motor tasks have shown that in patients with multiple sclerosis (MS), there is an increased recruitment of several regions part of a complex sensorimotor network. These studies have suggested that this might be the case because patients tend to activate, when performing a simple motor task, regions that are usually activated in healthy subjects during the performance of more complex tasks due to the presence of subcortical structural damage. In this study, we tested this hypothesis by comparing the patterns of cortical activations during the performance of two tasks with different levels of complexity from 16 MS patients and 16 age- and sex-matched controls. The first task (simple) consisted of flexion – extension of the last four fingers of the right hand, and the second task (complex) consisted of object manipulation. During the simple task, MS patients had, when compared to controls, more significant activations of the supplementary motor area (SMA), secondary sensorimotor area, posterior lobe of the cerebellum, superior parietal gyrus (SPG), and inferior frontal gyrus (IFG). These three latter regions are part of a fronto-parietal circuit, whose activation occurs typically in the contralateral hemisphere of healthy subjects during object manipulation, as shown also by the present study. During the performance of the complex task, MS patients showed an increased bilateral recruitment of several areas of the fronto-parietal circuit associated with object manipulation, as well of several other areas, which were mainly in the frontal lobes. This study confirms that some of the regions that are activated by MS patients during the performance of simple motor tasks are part of more complex pathways, recruited by healthy subjects when more complex and difficult tasks have to be performed. D 2003 Elsevier Inc. All rights reserved. Keywords: Multiple sclerosis; Cortical reorganization

* Corresponding author. Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy. Fax: +39-02-2643-3054. E-mail address: [email protected] (M. Filippi). Available online on ScienceDirect (www.sciencedirect.com.) 1053-8119/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2003.10.023

Introduction Although the last few years have witnessed a dramatically increased application of modern structural magnetic resonance (MR) techniques, capable to provide accurate estimates of the extent and severity of tissue damage, to the in vivo assessment of patients with multiple sclerosis (MS) (Filippi et al., 2002c), the strength of the correlation between clinical and MR imaging (MRI) findings remains moderate (Filippi et al., 2002c). One of the potential factors that has been considered to explain this discrepancy between clinical and MRI findings is the presence of functional cortical changes, which might contribute to the maintenance of a normal level of function, despite the presence of widespread tissue damage (Filippi et al., 2002a; Lee et al., 2000; Reddy et al., 2000a, 2002; Rocca et al., 2002a). Conversely, the inefficiency of the adaptive properties of the cortex might be an additional factor responsible for the accumulation of MS irreversible disability (Filippi et al., 2002b; Rocca et al., 2002b). Against this background, functional magnetic resonance imaging (fMRI) studies of MS have been performed, mainly using simple motor tasks with the dominant hand. These studies have shown, in patients with MS, an increased recruitment of several brain regions, which are considered to be part of a complex sensorimotor network, which includes the primary and secondary sensorimotor cortices, as well as regions in the frontal and parietal lobes (Filippi et al., 2002a,b; Lee et al., 2000; Pantano et al., 2002a,b; Reddy et al., 2000a, 2002; Rocca et al., 2002a,b). Many of these studies also showed a strong correlation between the extent of functional cortical changes and several MRI metrics of structural tissue damage (Filippi et al., 2002b; Lee et al., 2000; Pantano et al., 2002b; Reddy et al., 2000a, 2002; Rocca et al., 2002a,b). This finding has been interpreted as evidence that cortical functional reorganization might yet be an additional factor with the potential to limit the clinical impact of MS-related subcortical injury. In other words, it has been suggested that MS patients, when performing a simple motor task, might tend to activate regions that are activated in normal individuals when performing complex tasks as a result of the presence of structural disease-related damage to the white matter. This hypothesis has never been tested directly.

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This study was planned to gain additional insight into the mechanisms of cortical functional reorganization in MS. To this aim, we analyzed and compared the patterns of movement-associated cortical activations following two tasks with different levels of complexity, using fMRI and a general search method.

Patients and methods

controls were trained before performing the experiments. For the complex task, the subjects were instructed to perform always the same manipulation movement for all the objects using the rubber ball as training and to explore the object basic feature (surface, roughness, edge). To avoid visual stimulations, subjects were wearing an eye-mask during the experiments. They were also monitored visually during scanning to ensure accurate task performance and to assess for additional (e.g., mirror) movements. Tasks were performed equally well by all subjects.

Patients fMRI acquisition We studied 16 consecutive right-handed patients with relapsing – remitting MS (Lublin and Reingold, 1996). There were 13 women and 3 men; their mean age was 36.4 years (range = 18 – 60 years), median disease duration was 7 years (range = 2 – 17 years), and median Expanded Disability Status Scale (EDSS) score (Kurtzke, 1983) was 1.0 (range = 0.0 – 3.0). At time MRI was performed, all patients had been relapse- and steroid-free for at least 6 months. None of the patients had had previous relapses involving the right upper limb. Fourteen patients were treated with immunomodulatory drugs (three of them were treated with glatiramer acetate and the other 11 patients with one of the three available types of interferons beta). Sixteen sexand age-matched right-handed healthy volunteers with no previous history of neurological dysfunction and a normal neurological exam served as controls (13 women and 3 men, mean age = 34.6 years, range = 24 – 62 years). All subjects were assessed clinically by a single neurologist who was unaware of the MRI and fMRI results. Local Ethical Committee approval and written informed consent from all subjects were obtained before study initiation. Functional assessment Motor functional assessment was performed for all individuals on the same day MRI was acquired, using the nine-hole peg test (9HPT) and the maximum finger tapping frequency (Herndon, 1997). The maximum finger-tapping rate was observed for two 30-s trial periods outside the magnet, and the mean frequency to the nearest 0.5 Hz entered the analysis. Experimental design Using a block design (ABAB), where five periods of activation were alternated with six periods of rest (each period of activation and rest consisting of five measurements), the subjects were scanned while performing two different motor tasks. The first one consisted of repetitive flexion – extension of the last four fingers of the right hand moving together alternated to epochs of rest (simple task). The movements were paced by a metronome at a 1 Hz frequency. The second task consisted of manipulation of various daily life objects (i.e., a pen, a glass, a toothbrush, etc.) as compared to manipulation of a ‘‘neutral’’ object (a rubber ball) (complex task). The objects were passed on to the individual that was performing the fMRI experiment by an observer that remained in the scanner room during the entire fMRI acquisition. This observer was trained to pass the objects with the same rate in all the subjects and received visual commands by another observer in the MR console room. The order of the tasks was randomized across subjects. Patients and

Brain MRI scans were obtained using a magnet operating at 1.5 T (Vision, Siemens, Erlangen, Germany). Sagittal T1-weighted images were acquired to define the anterior – posterior commissural (AC – PC) plane. Functional MR images were acquired using a T2*-weighted single-shot echo-planar imaging (EPI) sequence (TE = 66 ms, flip angle = 90j, matrix size = 128  128, field of view [FOV] = 256  256 mm, TR = 3 s). Twentyfour axial slices, parallel to the AC – PC plane with a thickness of 5 mm, covering the whole brain were acquired during each measurement. Shimming was performed for the entire brain using an auto-shim routine, which yielded satisfactory magnetic field homogeneity. Structural MRI acquisition On the same occasion and using the same magnet, the following images of the brain were also obtained: (1) dual-echo turbo spin echo (TSE) sequence (TR = 3300, TE first echo = 16, TE second echo = 98, echo train length = 5, FOV = 250  250, matrix size = 256  256, 24 axial slices, slice thickness = 5 mm); (2) sagittal T1-weighted 3D magnetization-prepared rapid acquisition gradient echo (MP-RAGE) sequence (TR = 11.4 ms, TE = 4.4 ms, flip angle = 15j, FOV = 256  256, matrix size = 256  256, slab thickness = 160 mm, voxel size = 1  1  1 mm3). 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 the statistical parametric mapping (SPM99) software developed by Friston et al. (1995). Before statistical analysis, all images were realigned to the first one to correct for subject motion, spatially normalized into the standard space of SPM, and smoothed with a 10-mm, 3D-Gaussian filter. Structural MRI post-processing All the structural MRI analysis was performed by a single experienced observer, unaware to whom the scans belonged and blinded to the fMRI results. Brain lesions were identified on the proton-density (PD) weighted scans and marked on the hardcopies. The corresponding T2-weighted images were always used to increase confidence in lesion identification. Then, lesion volumes were measured using a segmentation technique based on local thresholding, as previously described (Filippi et al., 2001).

M. Filippi et al. / NeuroImage 21 (2004) 1147–1154 Table 1 Activation sites from healthy volunteers and patients with MS during the performance of the simple task (one sample t test for each group) Activation sites

Healthy subjects SPM coordinates: X, Y, Z

t SPM Values coordinates: X, Y, Z

t Values

Ipsilateral cerebellum Contralateral cerebellum Ipsilateral SMC Contralateral SMC Bilateral SMA Contralateral thalamus Ipsilateral SII Contralateral SII Ipsilateral IFG Contralateral IFG Contralateral SPG Ipsilateral SPG Ipsilateral insula Contralateral insula

20,

10.02

16.17

52,

22

MS patients

14,

52,

22

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Differences of these fMRI metrics between patients and controls were assessed using a two-tailed Student’s t test for not-paired data. Correlations between fMRI metrics, dual-echo lesion load, and disability during the performance of the simple task were assessed using the Spearman Rank Correlation Coefficient.

Results 16,

70,

24

6.72

22,

70,

26 10.29

Functional assessment 58, 22, 44 56, 24, 46 36, 34, 62 2, 0, 56 14, 18, 2

8.59 13.36 13.08 10.75 11.0

48, 34, 54 54, 30, 48 38, 22, 60 2, 6, 58 12, 16, 6

11.54 16.74 14.68 14.52 9.04

50, 22, 16 46, 22, 24 60, 16, 26 58, 8, 26 – – 46, 6, 6 46, 4, 6

7.49 13.21 7.56 6.78 – – 9.96 11.25

54, 26, 18 58, 24, 16 52, 12, 12 56, 6, 26 8, 76, 54 20, 84, 42 49, 9, 4 48, 6, 2

8.09 13.44 8.95 11.97 8.0 7.34 12.93 8.84

SMC: primary sensory-motor cortex; SMA: supplementary motor area; SII: secondary sensory-motor cortex; IFG: inferior frontal gyrus; SPG: superior parietal gyrus. For further details, see text.

Statistical analysis Changes in blood oxygenation level dependent (BOLD) contrast associated with the performance of the motor tasks were assessed 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 by applying appropriate linear contrasts. Significant hemodynamic changes for each contrast were assessed using t statistical parametric maps (SPMt). The intra-group activations and comparisons between groups were investigated using a random-effect analysis (Friston et al., 1999), with one-sample or two sample t tests, as appropriate. We report activations below a threshold of P < 0.05 corrected for multiple comparisons. To achieve a more precise definition of the anatomical locations of activated regions in each individual, MP-RAGE images from each subject were coregistered with the corresponding fMRI data sets and normalized into the same standard space. Then, fMRI results were superimposed onto these high-resolution images and, using cluster analysis on a patient-by-patient basis (Poline et al., 1997), we evaluated the spatial extent, the coordinates of the centers of the activations, and the percentage signal changes in those areas with significantly different relative activations at group analysis. The correspondence between these coordinates and anatomical areas was established by converting the Montreal Neurological Institute (MNI) coordinates into the Talairach coordinates, using a software implemented by SPM users (mni2tal). The Talairach Daemon (http://ric.uthscsa.edu/projects/ talairachdaemon.html) was then used to define the anatomical locations of the activated regions at group analysis. A 3D anatomical atlas was also used to increase confidence in the definition of the anatomical locations of these areas (Duvernoy, 1999).

Time to complete the 9-HPT and finger-tapping rates were not significantly different between patients and controls (time to complete the 9-HPT: mean = 20.6 s, SD = 3.9 s for controls; mean = 22.8 s, SD = 2.6 s for patients; finger-tapping rate: mean = 3.9 Hz, SD = 0.8 Hz for controls; mean = 3.8 Hz, SD = 0.5 Hz for patients). Structural MRI All healthy volunteers had normal brain MRI dual-echo scans. In MS patients, the median T2 lesion load was 11.5 ml (range =

Table 2 Activation sites from healthy volunteers and patients with MS during the performance of the complex task (one sample t test for each group) Activation sites

Healthy subjects

Ipsilateral cerebellum Contralateral cerebellum Ipsilateral SII Contralateral SII Ipsilateral SFG Contralateral SFG Ipsilateral MFG Ipsilateral IPS Contralateral IPS Ipsilateral CMA Ipsilateral IFG Contralateral IFG Ipsilateral MOG Contralateral MOG Ipsilateral postcentral gyrus Contralateral postcentral gyrus Ipsilateral thalamus Ipsilateral MT/V5 Contralateral MT/V5

34,

SPM coordinates: X, Y, Z 44,

40

MS patients t SPM Values coordinates: X, Y, Z 8.29

32, 46, 44 13.61 32, 68, 30 13.42 62, 20, 26 5.30 62, 30, 26 4.88 34, 46, 24 4.54 34, 42, 28 6.05 28, 2, 58 9.28 24, 60, 56 5.57 22, 70, 44 5.03 4, 12, 48 7.86 48, 10, 22 9.28 52, 10, 28 7.25 54, 58, 12 6.24 50, 66, 12 10.02 34, 40, 64 9.60 46, 28, 44 16,

16, 6

54, 66, 8 52, 64, 2

8.74

38, 40,

56,

t Values

36

56,

8.32

34 12.44

62, 36, 14 6.60 60, 22, 16 5.20 42, 44, 26 6.27 38, 46, 28 5.83 36, 2, 56 11.26 32, 58, 56 5.55 24, 66, 48 5.29 4, 10, 36 7.82 52, 10, 26 7.64 50, 6, 34 10.71 52, 62, 12 8.75 50, 68, 10 9.65 46, 28, 38 15.50 36,

42, 60

5.40

10,

10, 8

5.17 7.47

58, 62, 2 54, 66, 0

11.09 8.81 8.65 7.28

SII: secondary sensory-motor cortex; SFG: superior frontal gyrus; MFG: middle frontal gyrus; IFG: inferior frontal gyrus; IPS: infraparietal sulcus; CMA: cingulate motor area; MOG: middle occipital gyrus. For further details, see text.

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Fig. 1. Relative cortical activations in patients with MS during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands. Compared to healthy volunteers, MS showed increased recruitment of the ipsilateral supplementary motor area (A), superior parietal gyrus, bilaterally (A), contralateral SII (B), contralateral inferior frontal gyrus (B), and ipsilateral cerebellum, in a region located in the inferior semilunar lobule (C).

2.1 – 33.4 ml). No correlation was found between structural MRI metrics and clinical findings. Functional MRI: between-group analysis In Tables 1 and 2, the brain areas with significant activations detected while performing each of the two tasks in healthy subjects and MS patients are reported, along with the corresponding SPM space coordinates and t values. Simple task Compared to healthy volunteers, MS patients had more significant activations of the ipsilateral supplementary motor area (SMA) (SPM space coordinates: 4, 12, 42; corrected P value < 0.0001), contralateral secondary sensorimotor area (SII) (SPM space coordinates: 56, 20, 2; corrected P value < 0.0001), ipsilateral cerebellum, in a region located in the inferior semilunar lobule (SPM space coordinates: 40, 72, 36; corrected P value < 0.001), superior parietal gyrus (SPG), bilaterally (SPM space coordinates: 20, 84, 42, and 8, 76, 54; corrected P value = 0.01), and contralateral inferior frontal gyrus (IFG) (SPM space coordinates: 58, 10, 26; corrected P value = 0.004) (Fig. 1). For the IFG, MS patients also had an increased percentage signal change when compared to healthy volunteers (IFG percentage signal change: 1.17 in MS patients vs. 0.74 in healthy volunteers; P = 0.04). No significant differences were found in spatial extent and coordinates of centers of activations of all the above-reported areas between patients and controls. In patients with MS, the reported fMRI activations were not found to be significantly associated to the degree of clinical disability and the dual-echo lesion load. Complex task Compared to healthy volunteers, MS patients had more significant activations of the SII, bilaterally (SPM space coordinates: 60, 8, 4, and 64, 6, 6; P < 0.0001), the anterior (SPM space

coordinates: 4, 42, 32; corrected P value < 0.001) and posterior (SPM space coordinates: 2, 30, 44; corrected P value < 0.001) contralateral cingulate motor area (CMA), bilateral cerebellum, in a region located in the inferior semilunar lobule (SPM space coordinates: 40, 74, 36, and 20, 86, 26; corrected P value < 0.001), superior frontal gyrus (SFG), bilaterally (SPM space coordinate: 28, 42, 40, and 28, 52, 32; corrected P value < 0.001), ipsilateral MFG (SPM space coordinates: 48, 34, 32; corrected P value < 0.001), ipsilateral IFG (SPM space coordinates: 48, 26, 12; corrected P value < 0.001), and contralateral inferior parietal lobule (IPL) (SPM space coordinates: 42, 56, 44; corrected P value < 0.001) (Fig. 2). No significant differences were found in percentage signal changes, spatial extent, and coordinates of centers of activations of all these areas between patients and controls. Between task comparison In Tables 3 and 4, the brain areas with significant different activations at the within-group comparisons of complex versus simple task are shown. Between-group comparison of simple versus complex task Compared to healthy volunteers, MS patients had more significant activations of the contralateral IFG and SII, ipsilateral posterior lobe of the cerebellum and of the SPG, bilaterally. All these areas were significantly activated at a threshold of P < 0.001 (corrected for multiple comparisons), and had the same coordinates of the activations reported above (Table 3). Between-group comparisons of complex versus simple task Compared to healthy volunteers, MS patients had more significant activations of the ipsilateral MFG and postcentral gyrus, as well as of the anterior portion of CMA, SFG, and MOG, bilaterally. All these regions were significantly activated at a threshold of P < 0.001 (corrected for multiple comparisons),

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Fig. 2. Relative cortical activations in patients with MS during the performance of a complex motor task with their clinically unimpaired and fully normal functioning upper right hands. Compared to healthy volunteers, MS patients showed increased recruitment of the anterior (B, C) and posterior (A, B) cingulate motor area, contralateral inferior parietal lobule (A), SII, bilaterally (D), superior frontal gyrus, bilaterally (A – C), ipsilateral middle frontal gyrus (C), ipsilateral inferior frontal gyrus (E), and inferior semilunar lobule of the cerebellum, bilaterally (F).

and had the same coordinates of activations reported above (Table 4).

Discussion Object manipulation in humans is one of the hallmarks of motor dexterity. This task implies not only the ability to generate finger movements, but also the ability to integrate sensorimotor processing to achieve an accurate control of finger movements. This task involves extensive connections between the frontal and parietal lobes and the motor areas. Recently, using fMRI, Binkofski et al. (1999) have shown a grasping – manipulation circuit in humans, which includes the IFG (Brodmann area [BA] 44), the IPS, the SII, and a portion of the superior parietal lobe. We used a similar experiment to investigate the same circuit in patients with MS and a preserved function of the right upper limb. Several previous studies showed that when compared to healthy volunteers during the performance of a simple motor task with the dominant hand, MS patients have an extensive recruitment of sensorimotor and integration areas part of a rather widespread cortical network (Filippi et al., 2002a,b; Lee et al., 2000; Pantano et al., 2002a,b; Reddy et al., 2000a, 2002; Rocca et al., 2002a,b). In this study, we

wished to test the hypothesis that in MS patients, when performing a simple motor task, there is an increased recruitment of brain regions that might be activated in healthy volunteers during the performance of more difficult and complex tasks. During the performance of the simple task, MS patients had an increased activation of the SMA, SII, the posterior lobe of the cerebellum, the SPG, and the IFG. The SMA is an important component of the cortical motor network, which contributes to preparation, coordination, temporal course, and execution of movements (Lee et al., 1999; Ohara et al., 2000; Sadato et al., 1997). An increased recruitment of the SMA and the prefrontal cortex, including the IFG, in MS patients during the performance of simple motor tasks has already been demonstrated and has been seen to be related to the extent of tissue abnormalities (Lee et al., 2000; Reddy et al., 2000a; Rocca et al., 2002a). The SMA and the IFG might influence finger movements either through a direct action of the motor neurons of the spinal cord (Dum and Strick, 1996; He et al., 1993) or, indirectly, via corticocortical connections to the corticospinal neurons of the primary SMC (Tokuno and Tanji, 1993). SII is known to have extensive connections with the prefrontal cortex, the parietal lobe, and the insula (Friedman et al., 1986). The activation of this neuronal circuit has been demonstrated in healthy subjects during object manipulation (Binkofski et al.,

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Table 3 Within-group comparison of simple versus complex task activations in healthy volunteers and patients with MS (paired t test in each group) Activation sites

Primary SMC Anterior lobe of cerebellum SMA Insula – basal ganglia IFG SII

Healthy subjects

contralateral ipsilateral contralateral ipsilateral contralateral ipsilateral contralateral contralateral ipsilateral

MS patients

SPM coordinates: X, Y, Z

P values

SPM coordinates: X, Y , Z

P values

36, 12, 6, 12, 24, 22, – –

<0.0001 <0.0001 <0.0001

30, 28, 54 12, 50, 28 0, 10, 58

<0.0001 <0.0001 <0.0001

<0.0001 0.01 – –

42, 46, 60, 40, 48,

<0.0001

18, 50 44, 28 6, 56 8, 52 8, 2 8, 2

8, 4 2, 4 8, 12 24, 18 30, 22

<0.001 <0.0001 0.002

SMC: sensorimotor cortex; SMA: supplementary motor area; IFG: inferior frontal gyrus; SII: secondary sensory-motor cortex.

1999) and during precision grip task (Ehrsson et al., 2001). Its increased recruitment in MS patients during simple finger movements might be related to the increased activation of the prefrontal cortex and might modulate and control the force and the direction of fine fingers movements. This interpretation also agrees with the increased activation of the SPG, which has been related to the elaboration of somatosensory modalities and has a well-demonstrated hand – finger representation (Binkofski et al., 1999). MS patients also had an increased activation of a region in the posterior lobe of the cerebellum. While the anterior lobe has a somatotopic organization of the ipsilateral movements (Nitschke et al., 1996), the posterior lobe has been related to motor imagery (Grafton et al., 1996) and motor learning (Sakai et al., 1998). Therefore, its increased recruitment during the execution of such a simple task might reflect learning of motor representation and the need for coordination of finger movements. Interestingly, the posterior lobe of the cerebellar hemisphere is interconnected with the SMA and the parietal cortex (Ehrsson et al., 2002; Schmahmann and Pandya, 1995). Thus, the increased activity of these areas is consistent with the increased recruitment of the fronto-parietal pathway of these patients.

The areas found to be overactivated in MS patients when contrasted to matched controls during the performance of a simple motor task are, at least partially, different among the various studies published on this topic (Filippi et al., 2002a,b; Filippi and Rocca, 2003; Lee et al., 2000; Pantano et al., 2002a,b; Reddy et al., 2000a, 2002; Rocca et al., 2002a,b). There are several plausible explanations for these discrepant results. First, a different amount of T2-visible lesions was located along the pyramidal tracts. Indeed, the presence of such lesions has been shown to influence significantly the extent of the activations of the contra- and ipsilateral primary SMC in patients with MS (Pantano et al., 2002b; Reddy et al., 2000b). Secondly, the presence and severity of MS-related microscopic brain damage, as detected using quantitative MR techniques, have been found to influence the degree of activity of several cortical and subcortical areas (Filippi et al., 2002b; Reddy et al., 2000a, 2002; Rocca et al., 2002a). Thirdly, the severity of clinical impairment also has the potential to affect fMRI results and modulate the movement-associated patterns of cortical activations (Reddy et al., 2002). All of this and the observation that movement-associated fMRI activations vary according to the clinical phenotypes of the disease (Filippi and Rocca, 2003)

Table 4 Within-group comparison of complex versus simple task activations in healthy volunteers and patients with MS (paired t test in each group) Activation sites

IPS Posterior lobe of cerebellum MT/V5 Thalamus IFG SFG CMA Postcentral gyrus IPL MOG

Healthy subjects

contralateral ipsilateral ipsilateral contralateral contralateral ipsilateral ipsilateral contralateral ipsilateral contralateral ipsilateral contralateral ipsilateral ipsilateral contralateral contralateral ipsilateral

MS patients

SPM coordinates: X, Y, Z

P values

SPM coordinates: X, Y, Z

24, 54, 54 16, 68, 60 30, 72, 50

<0.0001 0.003 0.004

26, 62, 56 30, 56, 56 40,

50, 64, 50, 54, 8 16, 14, 6 38, 8, 24

10

0.001 0.03 0.001 0.009

30, 42, 28

0.002

6,

0.001

30, 32

54,

56,

34

64, 8

P values 0.01 0.001 0.001 0.001

44, 8, 28 42, 8, 24 30, 42, 28 32, 40, 30

0.001 0.008 0.004 <0.0001

8, 8, 44 52, 20, 36 42, 34, 38 50, 68, 2 50, 62, 14

0.001 <0.0001 <0.0001 0.002 0.001

IPS: infraparietal sulcus; IFG: inferior frontal gyrus; SFG: superior frontal gyrus; CMA: cingulate motor area; IPL: inferior parietal lobule; MOG: middle occipital gyrus.

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suggest that different areas of the complex human sensorimotor network might be involved in different phases of MS, possibly as a result of accumulating tissue injury. During object manipulation, MS patients not only showed a widespread and bilateral recruitment of some of the areas already identified as active during the performance of the simple task (such as the SII, the posterior lobe of the cerebellum, the IFG, and the parietal lobe), but also of several other areas, mainly in the frontal lobe, such as the CMA, the SFG, and the MFG. The frontal cortex contains many areas contributing to the motor network (Picard and Strick, 1996; Rizzolatti and Luppino, 2001). The rostral portion of the frontal cortex has essentially cognitive function, whereas the caudal portion is related to the control of movements (Picard and Strick, 1996; Rizzolatti and Luppino, 2001). Therefore, these findings seem to indicate that in MS patients, what differentiates the execution of a simple from a complex motor task is predominantly an increased recruitment of the frontal lobe, and in particular, the portion of this lobe that is involved in motivation, planning, and timing of actions. To identify the activation patterns during the performance of the two tasks, we investigated which brain regions were active during each of the two tasks in healthy volunteers and in MS patients. During the performance of the simple task, both groups of individuals showed an increased activation of a ‘‘classical’’ motor network, including the primary SMC, the anterior lobe of the cerebellum, the SMA, and the basal ganglia – insula. MS patients had additional activation of the SII, bilaterally, and of the contralateral IFG, in a region that roughly corresponds to BA44. Studies in humans have shown that this latter region is important for encoding hand – object interaction (Grafton et al., 1996). This area is supposed to receive rich sensory information originating from the parietal lobe (including SII) and to use it for action (Grafton et al., 1996). Therefore, its increased recruitment in MS patients during a simple finger movement might be related to the need for an increased amount of sensorimotor integration to perform the simple task, possibly due to the perception of such a movement as a relatively complex task. During the performance of the complex task, both groups had increased activations of several regions in the frontal and parietal lobes and of MT/V5, the area of the temporal lobe devoted to visual motion processing (Barton et al., 1996). Interestingly, while for the majority of these areas, the activations in healthy volunteers were in the contralateral hemisphere; MS patients showed a bilateral activation. Several authors suggested the existence of a left hemisphere dominance for action selection (Schluter et al., 1998, 2001). Our finding of a bilateral activation of the motor network, when the task is likely to be perceived as particularly complex and difficult by MS patients, suggests that this motor circuitry might undergo plastic reorganization in the presence of brain structural damage. The anterior part of the IPS contains neurons that discharge in response to 3D object presentation and during grasping movements (Sakata and Taira, 1994), and it is connected to the IFG for control of action in object manipulation (Binkofski et al., 1999). This area has a central role for visuomotor integration (cross-modal information process) (Rizzolatti et al., 1997). Therefore, the increased activation of all these regions in controls and patients might be related to the need to convey all the sensorial pieces of information regarding the manipulated object (e.g., shape, size, and consistency) to the frontal and motor cortices to generate a continuous manipulative task and possibly, to recognize the object and its function. The CMA and the prefrontal cortex are usually considered to have a role in ‘‘higher order’’

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function, such as temporal planning of action and motivation, and are thought to convey inputs to the caudal areas of the frontal lobe, such as the IFG and BA44 to implement the motor representations (Rizzolatti and Luppino, 2001). Compared to controls, MS patients also had an increased activation of the postcentral gyrus, the IPL, and the MOG. The postcentral gyrus is the continuation of the IPS, and its activation during object manipulation has already been described. The lateral occipital complex (LOC) has been shown to play a central role in object recognition (in particular, in the identification of object shape) (Amedi et al., 2002). This region also has a significant object-related activation both for visual and tactile modalities (Amedi et al., 2002) and has been suggested to be connected with the IPS, thus providing important information for object recognition, in particular for achieving a 3D description of the objects (Amedi et al., 2002). Finally, the activity of the posterior parietal cortex has been correlated with movement planning (Murata et al., 1996; Sakata et al., 1995). In conclusion, this study demonstrates that in MS patients, during the performance of a simple motor task, a widespread recruitment of brain regions, part of which has a role in processing the sensorial amount of information needed to control the correct performance of a movement, does occur. When the task is more difficult, the role of cross-modal neurons and of the frontal lobe, and hence of motivation and planning, becomes predominant. Further studies are now warranted to elucidate whether such cortical reorganization takes places with similar characteristics following cerebral injuries other than that associated with MS and to assess how it evolves with accumulating tissue damage.

Acknowledgments This study was supported by a grant from Fondazione Italiana Sclerosi Multipla (FISM/2002/R/28).

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