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. 2003 Aug 27;20(2):51–58. doi: 10.1002/hbm.10128

Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of multiple sclerosis

Bertrand Audoin 1,2, Danielle Ibarrola 1, Jean‐Philippe Ranjeva 1, Sylviane Confort‐Gouny 1, Irina Malikova 2, André Ali‐Chérif 2, Jean Pelletier 1,2, Patrick Cozzone 1,✉
PMCID: PMC6872003  PMID: 14505331

Abstract

Recent functional magnetic resonance imaging (fMRI) studies have suggested that functional cortical changes seen in patients with early relapsing‐remitting multiple sclerosis (MS) can have an adaptive role to limit the clinical impact of tissue injury. To determine whether cortical reorganization occurs during high cognitive processes at the earliest stage of multiple sclerosis (MS), we performed an fMRI experiment using the conventional Paced Auditory Serial Addition Test (PASAT) as paradigm in a population of ten patients with clinically isolated syndrome suggestive of multiple sclerosis (CISSMS). At the time of the fMRI exploration, mean disease duration was 6.8 ± 3.3 months. We compared these results to those obtained in a group of ten education‐, age‐, and sex‐matched healthy controls. Subjects were explored on a 1.5 T MRI system using single‐shot gradient‐echo EPI sequence. Performances of the two groups during PASAT recorded inside the MR scanner were not different. Statistical assessment of brain activation was based on the random effect analysis (between‐group analysis two‐sample t‐test P < 0.005 confirmed by individual analyses performed in the surviving regions P < 0.05 Mann Whitney U‐test). Compared to controls, patients showed significantly greater activation in the right frontopolar cortex, the bilateral lateral prefrontal cortices, and the right cerebellum. Healthy controls did not show greater activation compared to CISSMS patients. The present study argues in favor of the existence of compensatory cortical activations at the earliest stage of MS mainly located in regions involved in executive processing in patients performing PASAT. It also suggests that fMRI can evidence the active processes of neuroplasticity contributing to mask the clinical cognitive expression of brain pathology at the earliest stage of MS. Hum. Brain Mapping 20:51–58, 2003. © 2003 Wiley‐Liss, Inc.

Keywords: fMRI, PASAT, multiple sclerosis, clinically isolated syndrome, cortical reorganization, brain

INTRODUCTION

MRI/MRS techniques have dramatically increased the understanding of the pathophysiology of multiple sclerosis (MS). However, they have not yet been able to determine the missing link between tissue impairment and clinical expression, especially at the early stage of the disease. Discrepancy between tissue impairment and clinical expression could be related to neuroplasticity, a property that allows the central nervous system (CNS) to adapt itself to various brain insults. Indeed, numerous PET and fMRI studies have provided evidence that cortical plasticity may contribute to functional recovery after stroke, tumor, or brain trauma [Cao et al., 1999; Caramia et al., 1998; Chen et al., 2002; Cramer et al., 1997; Levine et al., 2002]. Adaptive cerebral plasticity of the cortical motor system may also limit the clinical expression of tissue impairment in MS [Filippi et al., 2002a,b; Lee et al., 2000a,b; Pantano et al., 2002; Reddy et al., 2000; Rocca et al., 2002; Staffen et al., 2002; Yousry et al., 1998]. This cortical motor reorganization would be present as soon as the earliest stage of MS, in patients with clinically isolated syndrome suggestive of MS (CISSMS) [Pantano et al., 2002]. At that stage, cerebral plasticity may contribute to maintain normal motor performance despite tissue damage [Pantano et al., 2002].

It appeared relevant to also undertake an anatomo‐functional study centered on more general cognitive processes like memory, attention, or information processing. Indeed, frequency of cognitive dysfunction is high in MS, present in nearly half of patients, as soon as at the early stage of the disease, even in subjects with low disability [Amato et al., 1999; Bagert et al., 2002; Dujardin et al., 1998; Rao et al., 1991]. Dysfunction frequently concerns information processing speed and recall of recently learned verbal or visual information, one aspect of memory [Amato et al., 1999; Bagert et al., 2002; Dujardin et al., 1998; Rao et al., 1991].

A recent study reported the existence of compensatory cortical activation observed during a complex cognitive task, in patients with clinically definite relapsing‐remitting MS [Staffen et al., 2002]. Compared to controls, a larger recruitment of brain regions implied in sustained attentional processes was observed in these patients performing the paced visual serial addition test (PVSAT) [Staffen et al., 2002], a visual entry version of the Paced Auditory Serial Addition Test (PASAT) [Gronwall, 1977]. Conventional PASAT has been included in the Multiple Sclerosis Functional Composite (MSFC) score and is recommended as an outcome measure in clinical trials for the cognitive evaluation of MS patients [Cutter et al., 1999; Fischer et al., 1999]. Cognitive processes involved in PASAT and in PVSAT may be slightly different with regard to the different scores of MS patients performing these two tasks [Diamond et al., 1997].

In this study, we aimed to determine if, as reported in the motor system [Pantano et al., 2002], cortical reorganization can occur in high cognitive systems at the very earliest phase of MS, namely in patients with CISSMS. To address this issue, we performed an fMRI experiment in a population of CISSMS patients, using as paradigm a conventional PASAT. Results of the 10 patients were compared to results obtained in a group of 10 healthy controls.

SUBJECTS AND METHODS

Subjects

We explored a group of ten patients with CISSMS fulfilling at inclusion at least the dissemination in space criteria according to McDonald (dissemination in space demonstrated by MRI, or positive CSF plus two or more MRI detected lesions consistent with MS) [McDonald et al., 2001]. Eight patients had a diagnosis of MS and two had a diagnosis of “possible MS” according to the McDonald's criteria when comparing the first MRI performed after relapse and conventional MRI performed at the same time as fMRI exploration (at least 3 months after onset and steroid treatment). Functional status of subjects was evaluated using the expanded disability status scale (EDSS) [Kurtzke, 1983] and the multiple sclerosis functional composite (MSFC) score [Cutter et al., 1999; Fischer et al., 1999] (Table I). Ten education‐, age‐, and sex‐matched healthy controls were also enrolled in this study. Comparison of group characteristics are summarized in Table II. The control group was used as the reference population for the calculation of the MSFC score. All subjects (patients and controls) were right‐handed (>70% Olfield scale) [Oldfield, 1971], first‐language French speakers, and naive people with respect to the PASAT. They gave their informed consent for their participation to this protocol approved by the local ethics committee (Timone Hospital, Marseille, France).

Table I.

Individual characteristics of patients with clinically isolated syndrome

Patient Age (yrs) Clinical syndrome McDonald's criteria Months since onset EDSS MSFC T2 lesion load (cm3)
1 36 Brainstem syndrome MS 4 1 −0.51 6.58
2 22 Optic neuritis MS 7 1 −0.92 1.54
3 22 Spinal cord syndrome MS 4 2 0.66 0.8
4 35 Brainstem syndrome MS possible 7 0 −0.31 3.10
5 40 Brainstem syndrome MS possible 5 1 0.63 1.64
6 36 Optic neuritis MS 3 1 −0.82 4.24
7 38 Optic neuritis MS 11 1.5 −0.73 3.71
8 34 Brainstem syndrome MS 12 1.5 −0.47 2.87
9 19 Spinal cord syndrome MS 10 1.5 −0.16 1.22
10 34 Optic neuritis MS 5 1.5 −0.03 3.11
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Table II.

Characteristics of groups of patients and normal controls

Patients Controls Z‐score Significance (U‐test)
Total (females/males) 10 (9/1) 10 (8/2)
Age in years, mean (SD) 31.6 (7.57) 26.1 (7.88) −1.403 0.1607
Mean educational level in years (SD) 12 (2.625) 13.6 (2.503) −1.328 0.1843
Mean duration since the presenting symptom in months, mean (SD) 6.5 (3)
EDSS, median (range) 1.25 (0–2)
MSFC, mean (SD) −0.2687 (0.5594) −0.0897 (0.6973) −0.267 0.7898
PASAT (Z‐scores) 39.9 (−0.5409) 46.8 (−0.2692) −1.027 0.3044
T2 lesion load, mean (SD) (cm3) 4.1 (3.56)
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Stimuli and design

Two rest blocks (one before the PASAT task and the other before the control task) were used for conditioning subjects to the MRI scanner noise but were not directly used in the statistical analysis. The PASAT task consisted in an auditory entry series of 61 single‐digit numbers delivered every 3 seconds (PASAT 3). After delivery of each number (except the first), subjects were asked to overtly vocalize the result of the addition of the two last numbers heard. Performances of subjects were recorded by an investigator present in the examination room. The control task consisted in repeating each number of the series used previously. Subjects were held tightly in the scanner head coil, asked to close their eyes, and warned and aware of the importance of minimizing head motion during fMRI acquisition especially when vocalizing results or repeating numbers.

Data acquisition

Subjects were explored on a 1.5 T Magnetom Vision Plus system (Siemens, Erlangen, Germany) using single‐shot gradient‐echo EPI sequence (TE = 54 ms, bandwidth 1,470 Hz/pixel, 17 slices, 5 mm thickness, 0.5 mm distant factor, matrix = 1282, FOV= 2402 mm2, pixel size = 1.882 mm2). Absolute acquisition time for a block of 17 slices was 2.25 sec. In total, 180 blocks were acquired at a rate of one block every 3 sec. The two series of the 61 single‐digit numbers (stimulus duration = 500 msec) were delivered through a personal computer by using the Cool Edit Pro software (version 1.2, Syntrillium software corporation, Phoenix, AZ), every 3 sec during the intervals of silence (blank duration = 775 msec). A morphological volumic 3D‐MPRAGE (TE=4.7 msec, TR = 9.7 msec, flip angle = 12°, 128 partitions, matrix = 2562, isotropic voxel 1.253 mm3) was also acquired to superimpose statistical maps.

Data analysis

Images were post‐processed using the SPM99 software (Wellcome Institute, London, UK). After realignment, images were normalized (Montreal Neurology Institute, MNI coordinates), coregistered, and 8 mm smoothed with a Gaussian filter. Statistical group analyses were performed using the random‐effect analysis [Friston et al., 1999]. After obtaining a single image for each subject parameterizing the effect of interest, within‐group analysis (one sample t‐test P < 0.01) and between‐group analysis (two‐sample t‐test P < 0.005) were performed. Statistical analysis was also performed on individuals using the general linear model and the theory of Gaussian random fields [Friston et al., 1995] to quantify activations in regions surviving to the random effect between‐group analysis. Voxel‐wise t statistics were normalized to Z‐scores to provide a statistical measure of activation between PASAT and Repeat independent of sample size. Activation threshold in individual analyses was set to P < 0.005 (uncorrected for multiple comparisons).

These individual results obtained in the predefined regions of interest were used to evaluate significance of the difference in brain activation between patients and controls using a Mann‐Whitney U‐test (P < 0.05).

MNI coordinates were transformed in Talairach's coordinates using a nonlinear transformation (online at http://www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html). Activation clusters were then assigned as Brodmann areas.

RESULTS

Individual characteristics of patients are summarized in Table I.

PASAT scores of the two groups recorded inside the MR scanner were statistically not different (P = 0.3044, Mann Whitney U‐test, see Table II). Brain areas with significant activations in healthy controls and CISSMS patients are summarized in Table III.

Table III.

Activations sites in healthy controls and CISSMS patients (PASAT‐REPEAT contrast, Random Effect Analysis)*

Activations sites Healthy controls CISSMS patients
Talairach coordinate t Talairach coordinate t
x y z x y z
SMA (BA 6) 8 0 64 9.43 2 −13 62 3.60
0 3 52 5.67
Left premotor cortex (BA 6) −50 −8 51 5.99 −46 −1 46 4.04
Right premotor cortex (BA6) 44 0 41 4.94 9 12 64 2.85
28 8 40 3.35 13 4 66 3
49 3 27 4.99 32 8 47 3.32
Left premotor cortex (BA 8) −26 23 42 4.04 — — — —
−46 23 43 3.49
Right cingulate cortex (BA 24) 5 10 31 3.97 6 21 21 3.90
Left anterior cingulate cortex (BA 32) −7 21 26 3.61 −2 21 27 3.97
Left lateral prefrontal cortex
 (BA 46) −49 32 19 3.48 −43 46 18 3.81
  −47 47 7 2.96
 (BA 9/45) — — — — −45 31 32 3.51
  −41 5 31 3.39
Right lateral prefrontal cortex (BA 46) 43 30 25 5.65 59 33 10 3.32
Left ventrolateral prefrontal cortex (BA 47) — — — — −53 27 0 3.72
Right ventrolateral prefrontal cortex (BA 47) — — — — 53 21 −12 3.68
55 30 −12 3.15
Left frontopolar cortex (BA 10) — — — — −20 70 −3 3.73
Right frontopolar cortex (BA 10) — — — — 33 55 20 3.03
Left orbitofrontal cortex (BA 11) — — — — −46 50 −13 2.99
Left angular gyrus (BA 39) −35 −63 22 4.33 — — — —
Left precuneus (BA 7) −18 −54 67 3.41 0 −44 62 3.53
−6 −65 56 3.63
Right precuneus (BA 7) 21 −67 39 2.97 — — — —
Left superior temporal gyrus (BA 42/22) −69 −19 11 3.28 −66 −34 17 3.65
−67 −16 0 3.65
−65 −2 −1 3.13
Right superior temporal gyrus (BA 42) 65 −27 11 3.27 — — — —
Left fusiform gyrus (BA 37) −39 −74 −11 3.17 — — — —
−52 −43 −14 4.56
Right fusiform gyrus (BA 37) 60 −44 −20 4.04 — — — —
Left cerebellum — — — — −46 −62 −40 3.47
−28 −50 −38 3.62
−28 −70 −37 3.30
Right cerebellum — — — — 10 −80 −27 3.67
Left anterior thalamus −4 −3 12 6.48 — — — —
Right mesencephalum 6 −26 −6 6.52 — — — —
Right protuberance 6 −31 −35 5.10 — — — —
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*

SMA, supplementory motor area; BA, Brodmann Area (one sample t‐test P < 0.01, k = 5).

Compared to controls, patients showed significant greater activation in the right frontopolar cortex (BA 10), the right lateral prefrontal cortex (BA 45/46), the right cerebellum and the left lateral prefrontal cortex (BA 45/46) (P < 0.05, Mann Whitney U‐test) (Fig. 1 and Table IV). Healthy controls did not show greater activation compared to CISSMS patients.

Figure 1.

Figure 1

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Relative cortical activation during PASAT of CISSMS patients in comparison to healthy controls (two sample t‐test P < 0.005, k = 20). Significant differences (confirmed by individual statistics in these surviving regions P < 0.05 Mann Whitney U‐test) were obtained in the right frontopolar cortex (z = 19 mm), the bilateral lateral prefrontal cortices (z = 19 mm, z = 13 mm, and z = 7 mm), and the right cerebellum (z = 32 mm). Activation in the left frontopolar cortex was not significant according to the individual analysis (P = 0.091).

Table IV.

Differences of activation for patients and controls†

Sites Talairach coordinate Patients mean rank Controls mean rank Z‐score Significance (U‐test)
x y z
Right frontopolar cortex (BA 10) 19 63 13 13 8 −2.484 0.0130*
Left frontopolar cortex (BA 10) −32 63 3 12.2 8.8 −1.689 0.0912
Left lateral prefrontal cortex (BA 45/46) −56 26 13 12.65 8.35 −2.004 0.0451*
Right lateral prefrontal cortex (BA 45/46) 57 30 10 13.5 7.5 −2.796 0.0052*
Right cerebellum 10 −80 −27 13.85 7.15 −2.848 0.0043*
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†

BA, Brodmann Area.

*

Significance level: P < 0.05.

No significant correlations (Spearman rank) were observed between brain activation level and the whole brain T2 lesion load or between brain activation and subject score during PASAT.

DISCUSSION AND CONCLUSION

Previous fMRI studies have supported the existence of functional adaptive changes in MS patients during motor tasks [Filippi et al., 2002a,b; Lee et al., 2000a,b; Pantano et al., 2002; Reddy et al., 2000; Rocca et al., 2002; Yousry et al., 1998]. Generally, greater activations in patients have been observed in the ipsilateral and contralateral motor cortices [Filippi et al., 2002a,b; Lee et al., 2000a,b; Reddy et al., 2000; Rocca et al., 2002; Yousry et al., 1998]. These results have been interpreted as a consequence of the recruitment of vicarious systems inside the ipsilateral hemisphere and recruitment of new motor units inside the controlateral hemisphere. Such cortical reorganization could limit the clinical expression of tissue damage [Cifelli and Matthews, 2002, Filippi et al., 2002a,b; Lee et al., 2000a,b; Reddy et al., 2000; Rocca et al., 2002]. Cortical reorganization also exists in other networks implied in high cognitive processes. Indeed, a recent study described compensatory cortical activation in patients with clinically definite relapsing‐remitting MS during PVSAT in relation to a larger recruitment of brain regions implied in sustained attentional processes [Staffen et al., 2002]. This first study used a visual entry version of PASAT to suppress interferences between scanner noise and auditory stimuli [Staffen et al., 2002]. Cognitive processes involved in the performance of this modified version of the test may probably be slightly different from those recruited during a conventional PASAT and may explain, at least in part, differences in location of activated cortical regions observed in the present study. Indeed, absence of interference between storage of verbal information and vocalization of a result modifies the strategy employed by subjects. In the PVSAT, visual entry of stimuli removes an interference between output and input modalities, leading to higher performances of subjects as reported by others [Fos et al., 2000]. Differences between our results and those published by Staffen et al. [2002] may also be related to the different groups of patients studied (i.e., clinically definite MS vs. CISSMS).

By using as fMRI paradigm the PASAT, the generally accepted reference test for the cognitive evaluation of MS patients [Cutter et al., 1999], we showed that cortical reorganization can occur in high cognitive systems at the earliest phase of MS as it was previously demonstrated in the motor system in patients with CISSMS [Pantano et al., 2002]. We observed functional changes in CISSMS patients compared to controls performing PASAT while task performance recorded inside the MR scanner was not significantly different between the two groups. Recording responses of subjects during the fMRI acquisition allowed for obtaining the PASAT score without interferences of the habituation effect occurring when redoing the test outside the MR scanner. This allowed also for the control of a confounding effect related to the possible difference in performance between the two groups. These changes in cortical responses during PASAT were both quantitative (higher activation in patients compared to controls in the bilateral lateral prefrontal cortices) and topographical (recruitment of the right frontopolar cortex and the right cerebellum in patients) with no direct relation with the whole brain T2 lesion load. This could be related to the fact that, at the very earliest stage of MS, the extent of macroscopic tissue injury evaluated by the whole brain T2 lesion load does not reflect directly the actual extent of tissue damage that can only be assessed by more sensitive MR techniques like diffusion imaging, magnetization transfer imaging, or MR spectroscopy [Cercignani et al., 2000; De Stefano et al., 2001].

During PASAT, subjects are asked after delivery of each number to overtly vocalize the result of the addition of the two last numbers heard. Because subjects have to maintain (one number previously heard) and manipulate verbal information over a short period of time, this test is generally thought to be very demanding as regards verbal working memory processes [Armstrong et al., 1996; Fisk and Archibald, 2001]. In controls and patients, activations in the lateral premotor cortices (BA 6), the SMA (BA 6), the posterior part of the left superior temporal gyrus may be related to the recruitment of the phonological loop of verbal working memory [Baddeley 1986, 1992]. Functional imaging studies allowed for locating regions implied in inner speech, a component of the phonological loop, inside the supplementary motor area, the lateral premotor cortices, the Broca area (BA 44), and the right cerebellum [Della Sala et al., 1991; Fiez et al., 1996; Salmon et al., 1996; Shallice et al., 1994; Smith and Jonides, 1998]. Regions including the left supramarginalis gyrus (BA 40) and the posterior part of the left superior temporal gyrus (BA 42) have been associated with the phonological store [Paulesu et al., 1993]. In both groups, activations in the Broca's area and the left supramarginalis gyrus were probably removed by the relative similar effects of PASAT and the control task of repeating numbers in these regions classically implied in language. The greater activation inside the right cerebellum in CISSMS patients could be related to a compensatory larger recruitment of a component of the inner speech system during PASAT. This result could be interpreted in the light of previous studies [Litvan et al., 1988; Ruchkin et al., 1994] that suggested impairment of the phonological loop of working memory in clinically definite MS patients.

In this test where the stored object is a single‐digit number, difficulty is not directly linked to memory load but rather to maintain this short verbal information beyond a simple calculation task (result of the addition of the two numbers heard) and vocalize this result (interference between output and input modalities). These two interfering processes may involve preferentially the executing systems operating on the content of working memory. Large activations during PASAT were located in the bilateral lateral prefrontal cortices (BA 45/46) in the two groups. These regions have previously been reported as parts of the central executive system of working memory [D'Esposito et al., 1995, 2000; Petrides et al., 1993]. The lateral prefrontal cortex is recruited when monitoring and manipulation of information within the working memory is required [Owen et al., 1998; Petrides, 1994]. It has also been demonstrated that these regions were recruited for maintenance of information when this information must be shielded from concurrent distracting stimuli [Chao and Knight, 1998]. Thus, in CISSMS patients, higher activation of the lateral prefrontal cortices may be related to the greater recruitment of the central executive system of working memory. Increased brain activity in these areas may represent a compensatory mechanism that contributes to normal performance despite brain injury.

Another executive control is required to inhibit conflict of the prepotent calculation process corresponding to adding the last vocalized result to the last number heard. The activation of the anterior cingulate (BA 32) in patients and healthy volunteers during PASAT could be related to the inhibition of pre‐programmed response (adding the last number heard to the last result), while previous work showed the role of this region in experiments that induce cognitive conflicts [Bush et al., 1998; Smith and Jonides, 1999]. No significant differences between groups have been found in these areas.

Moreover, during PASAT subjects must perform the addition of one‐digit numbers. These simple calculus operations may not require arithmetic procedures but require the retrieval of arithmetic facts stored in long‐term memory [Ashcraft, 1992; Dehaene, 1992; McCloskey et al., 1985]. Activations were present in regions frequently reported in simple calculation and arithmetic procedure tasks, namely the bilateral precuneus (BA 7) observed in both groups and the left angular gyrus (BA 39) only observed in controls [Dehaene et al., 1996; Rickard et al., 2000; Zago et al., 2001]. We also found in controls an activation in the left fusiform gyrus (BA 37) probably related to visual representation of numbers [Dehaene et al., 2002]. No significant differences between groups have been found in such posterior regions.

Finally, patients recruited the right lateral frontopolar cortex (BA 10) during PASAT. This region is known to play a central role in higher cognitive functions such as planning, problem solving, and memory retrieval. Previous observations in reasoning or planning tasks suggested that the lateral frontopolar regions are recruited in tasks that maximize the demand in executive processing [Christoff et al., 2001]. Recently, Koechlin and colleagues [Koechlin et al., 1999] proposed that the lateral frontopolar regions may be particularly involved in tasks requiring the maintenance of primary task goals while simultaneously allocating attention to subgoals. During PASAT, subjects must keep verbal information in working memory (last number heard) and perform simultaneously a simple calculation task (addition of the two last numbers heard). Thus, subjects must continuously keep in mind the last number heard and retrieve in memory arithmetic facts. Although PASAT is not a typical branching task (because the two goals are not independent), these two simple goals could induce recruitment of frontopolar cortex in patients. Indeed, PASAT may require more cognitive effort for CISSMS patients than for healthy controls because of neural network damage.

To conclude, the present study indicates the existence of compensatory cortical activations mainly located in regions involved in executive processing at the earliest phase of MS, in CISSMS patients performing PASAT. It also suggests that fMRI can evidence the active processes of neuroplasticity contributing to mask clinical cognitive expression of brain pathology, even at the earliest stage of MS. fMRI could become a useful method to characterize early compensatory cortical reorganization in MS and could provide objective indices of brain function in the evaluation of the disease evolution.

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