Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 157-164, 15 February 2003

MRI–clinical correlations in the primary progressive course of MS: new insights into the disease pathophysiology from the application of magnetization transfer, diffusion tensor, and functional MRI

Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy

Article Outline

Abstract 

Despite patients with primary progressive multiple sclerosis (PPMS) experience a progressive disease course from onset, the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are lower than in all other main clinical phenotypes of MS. This review outlines the major contributions given by magnetization transfer MRI, diffusion tensor MRI and functional MRI to the understanding of the pathophysiology of PPMS and provides evidence that, at least, three factors might explain this clinical/MRI discrepancy: (a) the presence of a diffuse tissue damage at a microscopic level; (b) a prevalent involvement of the cervical cord, and (c) an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage.

Keywords:  Primary progressive multiple sclerosis, Magnetic resonance imaging, Magnetization transfer, Diffusion tensor, Functional magnetic resonance imaging

Abbreviations:  PPMS, primary progressive multiple sclerosis, MRI, magnetic resonance imaging, RR, relapsing remitting, SP, secondary progressive, MT, magnetization transfer, DT, diffusion tensor, NAWM, normal-appearing white matter, NAGM, normal-appearing gray matter, fMRI, functional magnetic resonance imaging, MTR, magnetization transfer ratio, ADC, apparent diffusion coefficient, D̄, mean diffusivity, FA, fractional anisotropy, ROI, region-of-interest, CSF, cerebrospinal fluid, NABT, normal-appearing brain tissue, BOLD, blood oxygenation level-dependent, CBF, cerebral blood flood, CBV, cerebral blood volume, EDSS, expanded disability status scale, SMA, supplementary motor area, SII, upper bank of the sylvian fissure, MFG, middle frontal gyrus, CMA, cingulate motor area

 

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1. Introduction 

Patients with primary progressive multiple sclerosis (PPMS) represent a subgroup of patients with clinical and magnetic resonance (MR) imaging (MRI) characteristics which differ from those of patients with relapsing–remitting (RR) MS and secondary progressive (SP) MS [1], [2]. Despite patients with PPMS experience a progressive disease course from onset, the burden and activity of lesions on their T2-weighted and gadolinium-enhanced brain MRI scans are, on average, lower than in all other main clinical phenotypes of MS [3], [4], [5], [6], [7], [8]. That the pathology of lesions in PPMS is characterized by a predominant loss of myelin and axons with only mild inflammatory components [9] can explain, at least partially, the relative paucity of conventional MRI-detectable activity [4], [5]. However, differently from the case of other disease phenotypes, in PPMS patients the correlation between MRI abnormalities and clinical disease severity is not significantly ameliorated when measuring the load of brain T1-hypointense lesions [7], [8], which are thought to reflect areas where severe tissue disruption has occurred [10]. Three factors might explain the discrepancy between brain MRI and clinical findings in PPMS. First, the presence of diffuse tissue damage at a microscopic level [11]. Second, a prevalent involvement of the cervical cord [6], [7], which might also explain the disproportion between the severity of locomotor disability and the less pronounced impairment of other functional systems [1]. Third, an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage [12], [13].

Magnetization transfer MRI (MT MRI) [14] and diffusion tensor MRI (DT MRI) [15] can provide metrics reflecting the extent of tissue damage with increased pathological specificity over conventional MRI. In addition, they enable us to quantify the severity of tissue pathology affecting the normal-appearing white (NAWM) and gray (NAGM) matter beyond the resolution of conventional MRI. Functional MRI (fMRI) holds substantial promise to elucidate the mechanisms of cortical adaptive reorganization following MS injury [12], [13], [16], [17], [18] and, as a consequence, opens new perspectives for the monitoring of the mechanisms underlying recovery or maintenance of functions in the presence of irreversible tissue damage. This review outlines the major contributions given by MT MRI, DT MRI and fMRI to the understanding of the pathophysiology of PPMS.

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2. Basic principles of MT MRI, DT MRI, and fMRI 

MT MRI provides an index, named MT ratio (MTR), which reflects the efficiency of the magnetization exchange between protons in tissue water (relatively free) and those bound to the macromolecules [14]. Such an exchange depends upon the relative concentrations of the two pools of protons and on their efficiency of interaction. Although, in MS, low MTR values may be caused either by a reduction in the integrity of macromolecular matrix reflecting damage to the myelin or to the axonal membrane [19], or by a dilution of the macromolecules brought about by inflammatory edema [19], a post-mortem study [20] has provided compelling evidence that marked reductions of MTR values in MS lesions and NAWM are strongly correlated with the percentage of residual axons and the degree of demyelination.

DT MRI allows quantitative measurements of different aspects of tissue microstructure, obtained by exploiting the properties of water diffusion in the brain [21]. The diffusion coefficient of biological tissues, which is influenced by their various components, including cell membranes and organelles, is always lower than the diffusion coefficient in free water, and, for this reason, is named apparent diffusion coefficient (ADC). Pathological processes which modify tissue integrity, thus resulting in a loss or increased permeability of “restricting” barriers to water molecular motion, can determine an increase of the ADC [22]. Since some cellular structures are aligned on the scale of an image pixel, the measurement of diffusion is also dependent on the direction in which diffusion is measured. As a consequence, diffusion measurements can give information about the size, shape, orientation and geometry of tissues [23]. A measure of diffusion which is independent of the orientation of structures is provided by the mean diffusivity (D̄), the average of the ADCs measured in three orthogonal directions. A full characterization of diffusion can be obtained in terms of a tensor [24], a 3×3 matrix which accounts for the correlation existing between molecular displacement along orthogonal directions. From the tensor, it is possible to derive D̄, equal to one-third of its trace, and some other dimensionless indexes of anisotropy. One of the most used is the fractional anisotropy (FA) [25]. Tissue disruption, by removing structural barriers to water molecular motion, typically causes increased D̄ and decreased FA values [24], [25]. Clearly, the pathological elements of MS have the potential to alter the permeability or geometry of structural barriers to water diffusion in the brain. Consistently with this, several in vivo DT MRI studies [26], [27], [28], [29], [30], [31], [32], [33] have reported increased D̄ and decreased FA values in T2-visible lesions and NAWM from MS patients.

The analysis of MT MRI and DT MRI scans can be conducted using a region-of-interest (ROI) approach or, on a more global basis, by producing histograms of MTR, D̄ or FA values from a given portion of tissue [34], [35]. The latter technique can be applied to the whole of the brain parenchyma, after removal of pixels belonging to cerebrospinal fluid (CSF) and extracranial tissue. Macroscopic MS lesions segmented on T2-weighted images can also be superimposed onto the co-registered MT MRI or DT MRI scans and the corresponding areas can be masked out, thus obtaining maps and histograms of MTR, D̄ or FA from the normal-appearing brain tissue (NABT) in isolation. Histograms of the gray and white matter in isolation can also be produced [36], [37]. MTR histogram analysis has also been applied to the study of the cervical cord and the corresponding MR metrics have been found to be correlated to MS disability [38].

fMRI is being widely used to study the neuronal mechanisms of central nervous system functioning, and to define abnormal patterns of brain activations arising from disease. The signal changes seen during fMRI studies depend on the blood oxygenation level dependent (BOLD) mechanism, which in turn involves changes of the transverse magnetization relaxation time — either T2* in a gradient echo sequence, or T2 in spin echo sequence. These changes are attributable to differences in deoxyhemoglobin subsequent to variations of neuronal activity [39]. The correlation between local deoxyhemoglobin levels and neuronal activity is thought to result from changes in oxygen extraction, cerebral blood flow (CBF), and cerebral blood volume (CBV) [39], all of which change with neuronal activity [40], [41], [42]. Activation of a given brain area produces an increase of the neuronal and glial metabolism, accompanied by an increase of the regional CBF of that area. Although not yet proven for all the stimuli, there is evidence that, initially, the oxygenation level of the blood drops slightly (“early response” or “initial dip”) [41]. This event is followed by an increase in both blood flow and oxygen concentration (“late” response). As a consequence, three effects can contribute to the fMRI signal changes: (a) an increase in the blood flow velocity, (b) an increase in the blood volume flow rate and (c) changes in the blood oxygenation level. Using fast MRI methods, the contribution of the last factor is maximized [43], [44]. Using a simple motor task, recent studies have shown that functional cortical reorganization does occur in patients with RRMS and SPMS and mainly involves the “classical” motor areas [12], [13], [17], [18]. The correlation between various measures of structural MS damage and the extent of the cortical activation consistently found by these studies [12], [13], [17] suggests a role for adaptive cortical changes in maintaining a normal level of functioning in patients with MS.

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3. Brain MT MRI studies of PPMS 

The first report of MT MRI findings in PPMS was that from Gass et al. [45], who studied 43 MS cases, of whom 10 were affected by PPMS, using a ROI analysis of T2-visible lesions and NAWM. The average lesion MTR was lower in PPMS patients than in subjects with small vessel disease, but no difference was found between PPMS and other MS clinical phenotypes. A significant, inverse correlation between lesion MTR and expanded disability status scale (EDSS) [46] scores was found for SPMS, but not for PPMS patients. More recently, Leary et al. [47] have used the same analysis method to compare NAWM MTR values from 52 PPMS patients with those from the white matter of healthy controls. The average MTR value from all the ROIs was significantly lower in patients than in controls. When comparing the individual anatomical sites, the difference between PPMS and controls was still significant for the corpus callosum, the centra semiovalia and the frontal lobe NAWM. A moderate inverse correlation (r=−0.35) was found between patients' EDSS and corpus callosum NAWM MTR. Both these studies support the hypothesis that, in PPMS patients, there is diffuse tissue damage in the NAWM, which might contribute, at least partially, to clinical disability.

Three cross-sectional studies [48], [49], [50] have compared brain MTR histogram findings from patients with the major clinical phenotypes of MS, i.e. PP, RR, benign and SP [51]. Filippi et al. [48] studied 10 PPMS patients and found that, among the MS subgroups, they had the lowest T2 and T1 lesion loads and the highest average lesion MTR, while the MTR histogram peak height was lower than in any other MS phenotype. In this study, formal statistics were based on a priori comparisons, whose nature was decided based on the patterns of MS clinical evolution. Therefore, findings from PPMS patients were compared with those from healthy controls and the MTR histogram peak height resulted to be significantly lower in the former than in patients with PPMS. Dehmeshki et al. [49] performed a similar study in a larger sample (46 cases) of PPMS patients and found no significant differences between PPMS and RRMS or SPMS patients as regards whole brain MTR histogram-derived quantities. There was no relationship between individual histogram metrics and the EDSS scores, whereas this was the case for RRMS and SPMS. However, when a principal component analysis using all the available histogram data was run, a moderate correlation emerged with clinical disability of PPMS patients (r=0.40). Kalkers et al. [50] investigated a subgroup of MTR histogram parameters thought to be more closely affected by partial volume averaging from enlarged CSF spaces in 79 MS patients, including 26 cases with PPMS. They found that these CSF-related MTR variables (reflecting the lower left portion of brain MTR histograms) were less altered in PPMS than in SPMS patients, whereas no significant differences between the two progressive forms of MS were found as regards the “parenchymal” MTR histogram-derived metrics. Significant correlations between clinical and MTR findings were found for relapse–onset, but not for PPMS patients [50].

Since, in all these studies [48], [49], [50], the whole of the brain tissue was used to produce MTR histograms, it is difficult to disentangle the relative contributions of MS damage occurring within or outside T2-visible lesions to the observed MTR changes in PPMS, although, given the relative low lesion burden generally observed in these patients, it is conceivable that a major contribution comes from the NABT. This has been confirmed by a preliminary study from Tortorella et al. [52], who obtained MTR histograms of the NABT in isolation. Despite the fact that only 10 PPMS patients were studied [52], a significant reduction of all the NABT MTR histogram-derived metrics, with the exception of the histogram peak position, was observed in comparison to healthy controls and, similarly to what was found for the whole of the brain tissue [48], the histogram peak height was lower in PPMS than in any other MS phenotype. Although a large extent of the NABT is constituted of NAWM and, as a consequence, diffuse NAWM damage is likely to be the major contributor to the observed MTR histogram changes, two preliminary studies have suggested that both NAWM and NAGM MTR are reduced in PPMS patients [37], [53].

A major limitation in interpreting the results of all the abovementioned studies [37], [48], [49], [50], [52], [53] is the relatively small size of the PPMS patient samples studied, which reflects the low prevalence of this phenotype in the overall MS population [1]. Against this background, we have recently conducted a cross-sectional study [54] in a cohort of 91 PPMS patients, whose conventional and MT MRI findings were compared with those from 30 age-matched healthy controls and 36 SPMS patients with similar levels of disability. According to recently developed diagnostic criteria for PPMS [55], about 85% of our patients were classified as having definite PPMS, indicating that there was a careful selection in order to exclude other neurological disorders which have the potential to mimic PPMS on clinical grounds. MTR histogram analysis confirmed the presence of diffuse abnormalities in the brain of PPMS patients, for whom the histographic quantities were all significantly lower than those of healthy subjects. The severity of global brain tissue damage was found to be similar in PPMS and SPMS patients. Although PPMS patients showed a significant decrease of brain parenchymal volume with respect to healthy controls, the results of group comparisons for MTR histogram-derived quantities did not change after correcting for this factor, thus indicating that brain atrophy per se does not affect the characteristics of MTR histograms a great deal. Differently from previous study [52], we did not find brain and NABT MTR histogram differences between PPMS and SPMS patients. This indicates that, in both PPMS and SPMS, the progressive reduction of cerebral tissue with “truly” normal MTR values accompanies the accumulation of irreversible disability, independently of the concomitant accumulation of MRI-visible lesions. In PPMS, this agrees with the frequent finding of diffuse T2 signal abnormalities in the brain and cervical cord [6]. In addition, in our sample of PPMS patients, average brain MTR values were only in part correlated with T2 and T1 lesion loads. The coefficients of these correlations were about −0.3, thus indicating that less than 10% of MTR variability was explained by the burdens of macroscopic lesions. All of this suggests that NABT pathology in PPMS does not merely reflect Wallerian degeneration of axons traversing macroscopic lesions [56], but it might be related to the occurrence of subtle pathology independent of larger lesions. Disappointingly, we did not find any correlation between individual brain or NABT MTR histogram-derived measures and the EDSS scores.

Another potential useful application of MT MRI in the study of PPMS is to provide paraclinical markers of the disease evolution over time, with the ultimate aim to monitor the efficacy of new experimental treatments. In a preliminary study, Filippi et al. [57] compared changes of T2 and T1 lesion load, brain and NABT MTR histogram-derived quantities over a period of 1 year in 96 patients with various MS phenotypes, including a subgroup of nine PPMS cases. Disappointingly, no significant changes of histographic quantities were observed in PPMS patients, while this was the case for SPMS patients. These data, albeit limited by the small size of the patient sample, suggest that brain MT MRI-derived measures are not sensitive enough to conduct clinical trials with relatively short follow-up periods in patients with PPMS.

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4. Cervical cord MT MRI studies of PPMS 

The technical difficulties in the acquisition of MT MRI scans from the cervical cord have recently been overcome and it is now feasible to obtain good-quality MTR maps from slabs of either sagittal or axial slices covering the entire cervical cord [38]. Cervical cord MTR histogram-derived metrics well differentiate MS patients from normal controls [38], [58], [59]. However, when RRMS patients are considered in isolation, cord MTR histogram characteristics are similar to those from healthy subjects [58]. That cervical cord MTR abnormalities might reflect the presence of irreversible MS damage is confirmed by the results of two preliminary studies comparing cervical cord MTR histograms from RRMS, SPMS and PPMS patients [58], [59]. Filippi et al. [58] found that PPMS and SPMS patients have similar cord histogram characteristics, even though fewer lesions were seen on the conventional MRI scans of patients with PPMS. Lycklama à Nijeholt et al. [59] reported that combining cervical cord MTR and cross-sectional area improves the strength of the correlation between cervical cord MRI findings and EDSS (r=−0.46). In addition, the correlation between brain MRI lesion burden and average cervical cord MTR, as well as those between brain and cord MTR histogram-derived quantities, have been found to be, at best, of moderate strength [60]. This indicates that the assessment of cervical cord damage using MTR histogram analysis can provide complementary information to those derived from the study of the brain, with the potential to increase our ability to explain the clinical manifestations of the disease.

This hypothesis has been investigated in our large-scale study comparing PPMS and SPMS [54], where both brain and cervical cord MRI and MT MRI scans were obtained from all the patients and healthy controls. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed and MTR histogram analysis was performed. We found a similar burden of cervical cord lesions in PPMS and SPMS patients, contrary to what was seen for the brain [6], [7], [54]. This finding underpins the importance of MS pathology in the cord in patients with progressive accumulation of disability, independent of the way this occurs, i.e. with or without preceding or superimposed relapses. The modest, inverse relationship we found between cord area and disease duration (r=−0.25) suggests that the development of cord atrophy might also be related to the time elapsed from the clinical onset of MS. This is also confirmed by the more pronounced degree of cord area reduction found in SPMS patients, who had an average longer disease duration than PPMS patients, but similar levels of disability. Cord MTR histogram findings from both PPMS and SPMS patients were abnormal, but cord MTR histogram peak height was significantly lower in the latter group, thus suggesting a major reduction in the proportion of pixels belonging to “truly” normal tissue. The lack of significant correlations we found between MRI or MT MRI measures of MS pathology in the brain and cord suggests that degenerative processes affecting fiber tracts descending from brain lesions play only a modest role in determining the severity of PPMS-related cervical cord pathology. Similar to what found for the brain [54], we did not find any correlation between individual cord conventional or MT MRI-derived measures and patients' EDSS. Only by combining cord measures reflecting the severity of atrophy (cross-sectional area at C2 level) and that of intrinsic pathology in the remaining tissue (MTR histogram peak height), we obtained a composite model with a relatively low (r=0.21), but significant correlation with clinical disability.

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5. DT MRI studies of PPMS 

In the last few years, an increasing number of DT MRI studies have been conducted in MS [26], [27], [28], [29], [30], [31], [32], [33], [35], [61]. However, only few of these studies included PPMS patients [27], [28], [31], [35]. Droogan et al. [31] compared the DT MRI characteristics of 35 MS patients with various clinical phenotypes (nine patients were affected by PPMS). In this study, brain coverage was limited to four to six central slices and a ROI-based analysis of MS lesions and NAWM was performed. No significant differences were found between MS clinical subgroups with regards to lesion or NAWM ADC and anisotropy indexes, nor there was a correlation between DT MRI findings and patients' disability. These findings have been confirmed by another, more recent report [28], where a larger brain coverage (10 slices) was achieved and 30 PPMS patients were studied. In this study [28], PPMS patients showed significantly higher D̄ and lower FA values than healthy controls in the NAWM of the corpus callosum and internal capsule, whereas this was not the case for RRMS and SPMS patients. In addition, no significant correlations were found between PPMS patients' EDSS and lesion or NAWM DT MRI findings, whereas, in the SPMS group, the strength of these correlations was moderate. These findings might indicate that, in PPMS, the loss of structural barriers to water motion in the internal capsule and the loss of fiber organization in the corpus callosum might contribute to the presence of severe locomotor disability and cognitive impairment, despite the paucity of MRI-visible abnormalities in these sites. In the study of Ciccarelli et al. [27], a DT MRI acquisition scheme allowing 21 brain slices to be obtained was used and ROI analysis of scans from eight PPMS patients was performed in the NAGM of basal ganglia and cerebellum and in the infratentorial and supratentorial NAWM. Again, no significant differences were found between MS subgroups. In PPMS, only a significant correlation between EDSS and infratentorial NAWM D̄ was found. Cercignani et al. [35] produced histograms of D̄ and FA values from a large portion of the central brain (i.e., including both T2-visible lesions and NABT) from 30 PPMS patients. All the histogram-derived quantities were significantly different between PPMS patients and healthy controls, but no differences were found among PPMS, RRMS and SPMS patients. In addition, no significant correlations were found between DT MRI findings and PPMS patients' disability, contrarily to what was seen for the other MS subgroups. Bozzali et al. [62] have obtained D̄ histograms of the NAGM from 102 patients with MS (35 patients had RRMS, 36 had SPMS, and 31 had PPMS) and 30 healthy controls. They found no significant difference for any of the D̄ histogram-derived metrics between controls and RRMS patients, whereas significant differences were found for mean D̄ and D̄ histogram peak location between controls and PPMS patients.

We have recently concluded a large-scale DT MRI study where findings from 96 PPMS patients were compared with those from SPMS patients and healthy subjects [63]. In this study, we produced histograms of D̄ and FA values from the brain tissue and, using a segmentation process based on FA thresholding [36], histograms of D̄ values from the NAWM and NAGM in isolation. We found that the average lesion D̄ was significantly higher in SPMS than in PPMS patients. Given this and the greater amount of brain tissue which is involved by T2-visible lesions in SPMS, in these patients the severity of intrinsic lesion damage might play an important role in the accumulation of irreversible disability. This agrees with longitudinal MT MRI data showing a progressive increase of tissue damage within newly formed lesions in patients with SPMS [64]. On the contrary, the low amount of T2-visible lesions and the observation that the severity of intrinsic tissue damage within individual lesions is lower in PPMS than in SPMS suggest that other factors, in addition to the presence of lesions affected by marked tissue disruption, should act in determining the dynamics of PPMS evolution. D̄ and FA histogram analysis from brain tissue showed that, in PPMS patients, the histographic quantities were all significantly different from those of healthy subjects. The severity of brain tissue damage was, however, found to be greater in SPMS than in PPMS patients. We found that both NAWM and NAGM D̄ histogram-derived quantities were different between PPMS patients and age-matched healthy subjects. Again, tissue damage in both these brain compartments was more pronounced in SPMS than in PPMS patients. Although these results indicate a net loss and disorganization of structural barriers to water molecular motion in the NAWM, we can only speculate on the possible pathological substrates and histopathological correlative studies are needed to clarify this issue. Nevertheless, subtle pathological changes are known to occur in the NAWM from patients with MS, including abnormally thin myelin and axonal loss [11], with the potential to determine increased D̄ values. Our results also confirm that, in PPMS, brain NAGM is not spared by the pathological process. There are at least two factors which may contribute to the increased D̄ values found in the NAGM of PPMS patients. First, the presence of discrete MS lesions, which go undetected when using T2-weighted imaging [65], [66]. Second, the presence of retrograde degeneration of gray matter neurons, secondary to the damage of fibers traversing MS white matter lesions [56]. However, the modest correlation (r=0.44) we observed between macroscopic lesion load and average NAGM D̄ suggests that the second mechanism is likely to account only for a limited part of DT MRI findings from the NAGM.

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6. fMRI studies of PPMS 

Our group has recently conducted two fMRI studies of patients with PPMS [67], [68] to investigate the potential for cortical reorganization in limiting the functional consequences of subcortical structural damage in these patients. Clearly, knowing to which extent cortical reorganization occurs in PPMS and whether it has an adaptive role might be rewarding in terms of improving our understanding of the pathophysiology of progressive disability in MS and in terms of planning treatment strategies for these patients.

In the first study [67], we assessed the patterns of brain activations following simple and complex motor tasks in 30 right-handed patients with PPMS and variable degrees of motor impairment and compared them with those from 15 right-handed, sex- and age-matched controls. We found significant cortical activation changes during both simple and complex motor tasks in PPMS patients in comparison with healthy controls. In addition, PPMS patients showed a different pattern of cortical activations according to their clinical impairment. During the performance of a simple motor task with clinically unaffected limbs, PPMS patients had larger and more significant activations of the contralateral supplementary motor area (SMA), the upper bank of the sylvian fissure (SII) bilaterally, and several regions of the frontal (bilateral middle frontal gyrus (MFG) and contralateral inferior frontal gyrus) and temporal (ipsilateral insula and superior temporal gyrus, bilaterally) lobes than healthy volunteers. During the performance of a simple task with an affected limb, PPMS patients showed increased activations of the ipsilateral cingulate motor area (CMA) and the ipsilateral postcentral gyrus. Finally, during the execution of a more complex task, PPMS patients showed increased activations of the ipsilateral thalamus, the MFG, bilaterally, and several other sensory regions.

Since efferents from the SMA project directly to the brainstem and the cervical cord, increased SMA activation in PPMS patients may represent recruitment of motor pathways that can function in parallel with the injured contralateral corticospinal tract [69]. The patients also showed increased CMA activation, a finding in normal subjects that is related to presentation of new motor tasks and perhaps a reflection of relative task difficulty [70], [71], [72]. However, the most novel and intriguing finding of the study was the demonstration of an increased activation of “non-motor” areas with simple motor tasks in patients with PPMS. These areas include the insula and several other areas located in the frontal, temporal, parietal, and occipital lobes. There is evidence that the insula is a multimodal convergence area [73] connected to several sensorimotor areas, including the primary sensorimotor cortex and the SMA [73], [74]. This suggests that sites for multimodal integration, which are not usually activated with a simple motor task, might be recruited to maintain functional capacity in response to tissue damage.

In the second study [68], we investigated, in 26 PPMS patients with a fully normal motor functioning of the right upper limb, whether movement-associated cortical activations, measured using fMRI, were correlated with brain and cervical cord structural damage, as measured using MT MRI and DT MRI. We reasoned that if cortical adaptive responses have the potential to limit the accumulation of disability in patients with PPMS after tissue injury, the extent of such changes should be greater with increasing volumes of T2-visible lesions, severity of intrinsic tissue damage of brain T2-visible lesions, NABT and cervical cord tissue. Consistently with this hypothesis, we found significant correlations (r values ranging from 0.59 to 0.68) between relative activations of several sensorimotor and multimodal integration areas and the severity of structural damage of the brain and the cervical cord. These findings provide additional evidence for a link between subcortical white matter pathology and adaptive functional reorganization of the cortex in MS and suggest that cervical cord damage is an important factor in the complex process leading to accumulation of irreversible disability in PPMS, not only in terms of being a site of potentially disabling lesions, but also because structural cervical cord changes can induce cortical changes with the potential to limit the functional impact of the disease.

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7. Conclusions 

Several cross-sectional studies, using MT MRI and DT MRI, have consistently demonstrated that brain NAWM and NAGM are damaged in patients with PPMS. MT MRI studies of the cervical cord indicate that, whereas brain MS pathology may have different patterns in PPMS and SPMS, cord damage plays an important role in determining the irreversible accumulation of MS disability, independent of the way this occurs. fMRI studies showed that cortical functional changes do occur in patients with PPMS, and involve a widespread network usually considered to function in motor, sensory and multimodal integration processing. Although the role of cortical reorganization in limiting the functional impact of MS structural damage is still not definitively proved, our results support the concept that cortical adaptive responses may have an important role in compensating for tissue damage in MS. As a consequence, the rate of accumulation of disability in PPMS might not only be a function of tissue loss, but also of progressive failure of adaptive capacity of the cortex.

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PII: S0022-510X(02)00131-4

Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 157-164, 15 February 2003

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