Brain excitability changes in the relapsing and remitting phases of multiple sclerosis: a study with transcranial magnetic stimulation

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Abstract

Objective: Recent functional and imaging studies have substantially contributed to extend the concept of multiple sclerosis (MS), classically regarded as a disease limited to the myelin axonal sheath. Several findings, in fact, point to a parallel involvement of neuronal components of the central nervous system (CNS) in the course of MS. In the present study, therefore, we explored, in MS patients, some characteristics of central motor pathways related to changes of neuronal excitability as measured using transcranial magnetic stimulation (TMS).

Methods: Seventy-nine patients affected by relapsing-remitting (RR) MS were examined using single and paired TMS in order to assess excitability changes in the hand motor cortex occurring during relapse and/or remission of the disease. The analyzed parameters were: motor-evoked potential (MEP) threshold, silent period (SP), intracortical inhibition (ICI) with paired pulses from 1 to 6 ms interstimulus intervals (ISIs), and central motor conduction time (CMCT).

Results: The analysis of variance exhibited a strong correlation (P<0.001) between the clinical phase and the type of excitability changes: ‘relapsing’ patients showed increased threshold and reduced SP duration. ‘Relapsing’ patients also displayed a significant lack of normal intracortical inhibition (ICI). By contrast, ‘remitting’ patients showed a significant SP prolongation with normal motor thresholds.

Conclusions: The present findings reveal changes in cortical excitability that might play a role in the pathophysiology of MS symptoms. In particular, the relapsing phase of MS has been found to be associated with cortical hyperexcitability irrespective of the site of clinical manifestation or new plaque formation. These results might help to explain the puzzling picture of neurological symptoms observed in MS patients during different phases of the disease.

Significance: Alterations of neuronal components of the CNS play a role in MS.

Introduction

Recent functional and imaging studies have substantially contributed to extend the concept of MS, classically regarded as a disease limited to the myelin axonal sheath. Several findings, in fact, point to a parallel involvement of neuronal components of the central nervous system (CNS) in the course of MS (Sharma et al., 2001, Chard et al., 2002, Nicot et al., 2003), and also suggest that the beneficial action of the therapy with interferon can be attributed, at least in part, to the preservation of neuronal function (Narayanan et al., 2001).

Although magnetic resonance imaging (MRI) greatly improved the early diagnosis and the functional assessment of MS, evoked potentials still play an essential role in the clinical evaluation of the disease (McDonald et al., 2001). In particular, motor-evoked potentials (MEPs) form a technique capable of exploring the neuronal function of central motor pathways and represent, therefore, a non-invasive approach to the study of the alterations involving the neuronal compartment of the brain of MS patients (Rothwell et al., 1987, Rossini et al., 1989, Schriefer et al., 1989, Smith et al., 1989, Leocani and Comi, 2000, Schmierer et al., 2002).

Studies with transcranial magnetic stimulation (TMS) have shown that, besides a significant prolongation of the central motor conduction time (CMCT), frequent abnormalities in MS patients are represented by both an increased threshold of MEP excitability and abnormal duration of central silent period (SP) (Boniface et al., 1991, Caramia et al., 1991, Petajan and White, 2000).

To our knowledge, however, a correlation between the clinical phase of the disease and cortical excitability changes occurring in MS has never been performed nor systematically tested on each hemisphere by TMS. In so doing here, we aimed at assessing the relationship between the level of cerebral excitability and the relapsing or remitting phases of MS. Defining the clinical phase of the disease through neurophysiological criteria can also yield insights into the neurobiology of MS.

Section snippets

Subjects and methods

We studied 79 drug-free patients with relapsing-remitting (RR) MS (64 females and 15 males, aged 18–55 years), who were admitted to the neurological clinic of the University of Rome ‘Tor Vergata.’ Patient characteristics are summarized in Table 1, Table 2, Table 3, with a progressive numeration that ends in Table 3. The diagnosis of RR MS was established by clinical, laboratory and MRI criteria, and matched the criteria of Poser et al., 1983, McDonald et al., 2001. In all instances, patients

Results

Details and means with SD on patients’ clinical parameters are given in tabular analysis (Table 1, Table 2, Table 3). All patients were able to perform, as required, the muscle contraction during TMS, without evident signs of tiredness or discomfort.

Transient deterioration of sensory disturbances was the most frequent type of symptom linked with the clinical relapse followed by visual (diplopia, amaurosis and nystagmus) and pyramidal disturbances. Sphincter and memory complaints were only

Discussion

The main finding of the present study is that the relapsing phase of MS is associated with cortical hyperexcitability, irrespective of the site of clinical manifestation or new plaque formation.

TMS has proven to be important for diagnosing and monitoring the progression or the functional state of many neurological diseases (for reviews see Rossini and Rossi, 1998, Hallett, 2000). In the present study we used TMS to reveal excitability changes in RRMS patients as assessed by the analysis of

Acknowledgements

We are thankful to Dr Pasqualetti for statistical advice and Dr Mark Wilson Jones for English revision.

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