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The use of transcranial magnetic stimulation in diagnosis, prognostication and treatment evaluation in multiple sclerosis

Multiple Sclerosis and Related Disorders, Volume 4, Issue 5, September 2015, Pages 430 - 436

Abstract

Despite advances in brain imaging which have revolutionised the diagnosis and monitoring of patients with Multiple Sclerosis (MS), current imaging techniques have limitations, including poor correlation with clinical disability and prognosis. There is growing evidence that electrophysiological techniques may provide complementary functional information which can aid in diagnosis, prognostication and perhaps even monitoring of treatment response in patients with MS. Transcranial magnetic stimulation (TMS) is an underutilised technique with potential to assist diagnosis, predict prognosis and provide an objective surrogate marker of clinical progress and treatment response. This review explores the existing body of evidence relating to the use of TMS in patients with MS, outlines the practical aspects and scope of TMS testing and reviews the current evidence relating to the use of TMS in diagnosis, disease classification, prognostication and response to symptomatic and disease-modifying therapies.

Highlights

 

  • TMS has been applied to the study of various aspects of MS.
  • Different TMS paradigms can be used in this regard.
  • Practical aspects of TMS and specific paradigms are reviewed.
  • TMS may have applications in diagnosis, prognostication and disease classification.
  • TMS may be used to assess response to various MS therapies.

Keywords: Multiple Sclerosis, Evoked Potentials, Transcranial Magnetic Stimulation.

1. Introduction

Advances in brain imaging have revolutionised the diagnosis and monitoring of patients with Multiple Sclerosis (MS), but MRI has limitations in this context, including a poor correlation with clinical disability ( Bakshi et al., 2008 ) and prognosis ( Kappos et al., 1999 ). There is a growing body of evidence that electrophysiological techniques such as evoked potentials provide complementary functional information which can aid diagnosis, prognostication and monitoring of patients with MS ( Leocani et al., 2006 ). Transcranial magnetic stimulation (TMS) is a technique with a wide range of diagnostic and therapeutic uses in a number of neurological conditions ( Chen et al., 2008 ), including MS, but which is not widely used in clinical practice. This paper will review the current evidence relating to the use of TMS in patients with MS and discuss the potential for its future use in this domain.

1.1. Principles of transcranial magnetic stimulation (TMS)

TMS is a painless, non-invasive and well-tolerated means of interrogating the motor systems of the central nervous system ( Barker et al., 1985 ). It was developed as an alternative to transcranial electrical stimulation, which was often poorly tolerated because of the high currents which had to be used to overcome scalp impedance. A large, brief current is passed through a wire coil on the scalp which induces a strong but short-lasting magnetic field at right angles to the coil. This in turn excites cortical motor neurones, triggering an action potential which spreads trans-synaptically along the corticospinal pathways, and the resultant motor evoked potential (MEP) responses can be recorded in peripheral muscles.

Different TMS paradigms can be used to examine the motor system. These include single-pulse, paired pulse or repetitive TMS. Of these, single- and paired-pulse are most useful diagnostically whereas repetitive TMS is used with therapeutic intent (for example in the treatment of depression ( Lam et al., 2008 )) or in the rehabilitation setting ( Ren et al., 2014 ; Macdonell et al., 1991 ; Khedr et al., 2014 ) and is beyond the scope of this review.

Single- and paired-pulse TMS are used to measure a variety of parameters including the following: resting motor threshold (MT), MEP amplitude and latency, central motor conduction time (CMCT), MEP recruitment curves and measures of cortical excitability such as intra-cortical inhibition (ICI), facilitation (SICF & ICF) and the cortical silent period (SP). Many of these parameters have been shown to be modulated by various drugs and disease states, as well as the degree of relaxation of the target muscle. Practical aspects of these techniques will now be briefly outlined.

1.2. Motor Threshold (MT)

The MT is defined as the minimum stimulus intensity (expressed as a percentage of the maximum output of the stimulator) which produces a response of a certain peak-to-peak amplitude (usually ≥100 μV) in at least 50% of trials. The MT varies widely between and within individuals, depending on such factors as age, wakefulness, pharmacological influences and degree of relaxation. This variability may limit the utility of MT measurement as a useful parameter per se, but it must be measured in order to calculate and standardise stimulus intensities for other paradigms. In some individuals, MT can exceed the maximum output of the stimulator (which can be physiological or pathological) and may preclude further suprathreshold testing. In general, MT is lower for muscles of the upper limbs than for the lower limbs and trunk, possibly reflecting the stronger corticospinal connections and larger representation of the upper limb muscles in the motor homunculus. A side-to-side difference with a slightly lower MT in the dominant hemisphere is usual ( Macdonell et al., 1991 ; De Gennaro et al., 2004 ).

1.3. MEP amplitude and latency

The cortical MEP is measured by delivering a single suprathreshold stimulus (typically 120% of MT) over the motor cortex and recording from a peripheral muscle. Several parameters can be measured, including latency, amplitude and area. Of these, the onset latency is considered to be the most reproducible and is therefore used most frequently ( Kiers et al., 1993 ). Reliable estimation of amplitude requires consistent suprathreshold levels of stimulation to be delivered (typically around 170% of MT in a resting muscle), which often exceeds the maximum output of the stimulator and precludes further measurement. An amplitude ratio (compared to a peripherally-evoked CMAP) can be used to control for individual variations in peripheral CMAP amplitude. MEP latency is shorter and amplitude is larger if the motor cortex stimulus is given during voluntary contraction of the target muscle. These factors need to be considered when interpreting the results ( Kiers et al., 1993 ).

1.4. Central motor conduction time (CMCT)

CMCT to the upper limbs is calculated by subtracting the latency of a single stimulus delivered over the cervical spine (with the coil centred at C6) and to the lower limbs the latency of a single stimulus delivered over the lumbar spine (with the coil centred at L4) from the latency of the motor cortex MEP response, thereby eliminating the contribution of the peripheral nervous system and permitting the assessment of conduction between the motor cortex and cervical or lumbar spinal cord. This method is well-validated, reproducible and tolerable ( Samii et al., 1998 ).

1.5. MEP recruitment curves

Increasing intensity of stimulation with TMS typically produces an increase in MEP amplitude. Varying the intensity of stimulation permits assessment of different populations of neurones with a wider range of excitability and may therefore provide additional information about the strength of corticomotor neuronal projections ( Jorgensen et al., 2005 )

1.6. Paired pulse TMS: short-interval intracortical inhibition (ICI) and facilitation (ICF)

Paired-pulse TMS paradigms can be used to study cortical excitability at the level of cortical interneurons using conditioning and test stimuli applied at varying interstimulus intervals (ISI). At short interstimulus intervals the most commonly used technique involves a subthreshold conditioning stimulus (CS, typically delivered at 80% of resting MT) followed by a supra-threshold test stimulus (TS, typically delivered at 120% of resting MT). The mean MEP amplitude at each ISI is then compared to the mean amplitude when the test stimulus is delivered alone without a preceding conditioning stimulus. At ISIs of 1-5ms, the test response is inhibited and reduced in amplitude; this is the phenomenon of short-interval intracortical inhibition (SICI). SICI is believed to be mediated by GABAA receptors ( Kujirai et al., 1993 ). At ISIs of 7-30ms, the test response is facilitated and increased in amplitude; this is known as intra-cortical facilitation (ICF) and is thought to be mediated via the glutamatergic system ( Chen et al., 2008 ; Ziemann et al., 1996 ).

Another type of facilitation is produced at ISIs of 1.1–1.5 ms, 2.3–2.9 ms and 4.1–4.4 ms if a test stimulus at or above motor threshold is followed by a CS around threshold intensity (0.9–1.1 MT). This is known as short-interval intracortical facilitation (SICF) and is mediated by facilitatory interaction between I waves which takes place in the motor cortex at or upstream from the corticospinal neuron ( Tokimura et al., 1996 ; Ziemann et al., 1998) .

1.7. Long-interval Intracortical Inhibition (LICI)

At ISIs of about 50–200 ms, a suprathreshold CS given at the same intensity as the following TS decreases the test MEP amplitude compared with the TS alone. This is thought to reflect the actions of a different circuit of inhibitory cortical neurones and is probably mediated via GABAB receptors ( Chen et al., 2008 ).

1.8. The cortical silent period (CSP)

A single TMS pulse delivered during tonic contraction of the contralateral target muscle transiently interrupts voluntary EMG activity; the period of EMG silence is known as the cortical silent period and is believed to reflect GABA-mediated motor cortical inhibition. The duration of the silent period is variable depending on the intensity of stimulation given to evoke the MEP, the degree of muscular contraction and the muscle involved.

1.9. Other TMS parameters

This is not an exhaustive list of possible TMS parameters; there are a number of other applications which include combinations of central and peripheral stimulation such as the triple stimulation technique ( Magistris et al., 1999 ) and short- and long-latency afferent inhibition and the use of twin-coil paired central nervous system stimuli to opposite motor cortices which can be used to interrogate cortico-cortical motor connections ( Codeca et al., 2010 ).

1.10. TMS: safety considerations

TMS is generally well-tolerated, painless and safe. Minor side effects include headache which is usually transient. There are isolated case reports of seizure in association with TMS, including in three patients with MS (Kandler, 1990 and Haupts et al, 2004) and one patient with stroke ( Homberg and Netz, 1989 ), although in two of the three MS patients seizures occurred several weeks after magnetic stimulation and a causal link is therefore unproven. TMS is used to study patients with known or suspected epilepsy ( Badawy et al., 2007 ) with an incidence of provoked seizure of between 0 and 2.8% for single-pulse TMS and 0–3.6% for paired-pulse TMS ( Schrader et al., 2004 ).

1.11. TMS: technical considerations

TMS may be delivered via a standard coil, figure-of-eight or double cone coil and the waveform produced may be monophasic or biphasic ( Jalinous, 1991 ). In general, figure-of-eight coils produce more localised currents and allow for more selective stimulation than standard coils ( Jalinous, 1991 ). Different apparatus may be more suitable for different muscles, for example a circular coil is adequate for testing of facial and upper limb muscles, whereas lower limb muscles are best tested using a double cone coil ( Terao et al., 1994 ). The effect of the stimulus may vary according to changes in coil orientation ( Kammer et al., 2001 )and therefore consistency in terms of the apparatus used within and between testing sessions is important.

1.12. Applications of TMS Paradigms to MS Patients

TMS paradigms have been applied in the study of a variety of neurological diseases including epilepsy ( Badawy et al., 2007 ; Badawy et al., 2009 ; Macdonell et al., 2002 ), motor neurone disease ( Vucic et al., 2013 ), dementia ( Cantone et al., 2014 ), migraine ( Afra et al., 1998 ), Parkinson's disease ( Spagnolo et al., 2013 ) and stroke ( Liepert et al., 2005 ) as well as MS. The existing literature regarding the application of single- and paired-pulse TMS paradigms to MS patients will now be reviewed.

1.13. Diagnostic application of TMS

Early electrophysiological studies evaluated the diagnostic utility of CMCT in patients with MS (Ingram et al, 1988, Barker et al, 1987, and Jones et al, 1991). These showed fairly consistent results, with prolongation of CMCT in MS patients relative to controls being evident in most clinically affected muscles and a variable proportion of clinically unaffected muscles( Ingram et al., 1988 ; Jones et al., 1991 ; Kale et al., 2009 ; van der Kamp et al., 1991 ). The diagnostic reliability of these parameters as compared to the contemporaneous Poser criteria ( Poser et al., 1983 ) has been calculated at 0.83 for prolonged CMCT and 0.75 for a normal CMCT( Ravnborg et al., 1992 ). Thus CMCT may have potential uses in detecting clinically silent lesions to enhance diagnostic certainty.

The relative sensitivity and specificity of visual evoked potential (VEP) and motor evoked potential (MEP) in this context have been debated (Mayr et al, 1991, Ravnborg et al, 1992, Hess et al, 1987, Michels et al, 1993, Kandler et al, 1991, and Kandler et al, 1991). VEP latency appears to be significantly more sensitive than CMCT alone (89% vs. 58%) ( Kandler et al., 1991 ), and clinically silent lesions of the optic nerves are much more common than those of the pyramidal tracts (85% for optic nerves vs. 10% for pyramidal tracts). However, when MEP measurement takes into account a wider variety of abnormalities than just latency (i.e. area, amplitude and side-to-side differences) it increases in sensitivity for detecting clinically silent lesions ( Gagliardo et al., 2007 ). In comparison to VEP, measurement of CMCT is also technically more difficult, slightly harder for patients to tolerate, and in some patients with electrically inexcitable cerebral cortices, is altogether impossible. Furthermore, there is a much higher concordance rate between MEP and MRI than between VEP and MRI – and therefore a much lower chance of uncovering useful complementary information by the addition of this test.

TMS paradigms designed to examine cortical excitability have also been tested for diagnostic utility in patients with MS. Resting motor threshold, measured as a precursor to paired-pulse stimulation, gives a crude index of cortical excitability. Several authors have reported an increase in resting motor threshold in patients with MS relative to healthy controls (Ravnborg et al, 1992, Sahota et al, 2005, Caramia et al, 1991, Vucic et al, 2012, and Conte et al, 2009). A number of small studies have attempted to characterise patterns of cortical excitability in MS patients relative to controls, and have suggested a reduction in SICI ( Caramia et al., 2004 ), a reduction in SICF ( Ho et al., 1999 ) and an increase in LICI ( Claus et al., 1992 ). However, these parameters have not been sufficiently well-validated to give them a role in confirming MS diagnosis, and larger studies which are sufficiently powered to control for between-individual variability in these parameters are required.

1.14. TMS in the Classification of MS Subtype

The clinical detection of progressive MS, whether primary or secondary, may be challenging, and an objective marker of disease classification is highly desirable both to minimise the unnecessary use of immunotherapies and in order to identify suitable patients for clinical trials of neuroprotective agents. It might be supposed that a more functional measure of motor system activity (such as MEP/TMS) might provide complementary information to MRI and might aid in diagnosing progressive MS. To this end, Humm et al., (2003) studied 141 patients with RRMS, PPMS and SPMS and measured CMCT with a number of other parameters. They reported a marked increase in CMCT in the group with progressive MS (SPMS and PPMS combined), independent of disease duration, number of spinal lesions or clinical motor deficit. Facchetti et al., (1997) also demonstrated a significant increase in CMCT, correlating with EDSS and pyramidal Functional System score, as well as a higher incidence of abnormal SSEP, MEP and BAEP in patients with SPMS when compared to those with RRMS and to healthy controls.

A small body of literature exists regarding the use of PPTMS in disease classification, stemming from the idea that progressive MS (PPMS and SPMS) may result from cortical dysfunction and neurodegeneration and might therefore be associated with more pronounced abnormalities when paired-pulse paradigms are used. Vucic ( Vucic et al., 2012 ) studied a group of patients with RRMS (n=25) and SPMS (n=15) and reported a reduction in SICI (as well as an increased MT) in SPMS patients relative to RRMS patients and healthy controls. Furthermore, there was a significant negative correlation between disability (EDSS score), SICI and MEP amplitude, and a significant positive correlation between EDSS score, resting motor threshold and CMCT. Association with radiological parameters was less robust, with only CMCT correlating with T2 lesion load. EDSS could be reliably predicted using a model which incorporated SICI and CMCT. Mori et al. (2013 ) studied 89 patients with MS of various types and reported a correlation between EDSS score and resting motor threshold and SICF which did not clearly differ according to MS disease type(as well as MEP latency, which did, being longer in SPMS relative to RRMS). Conte et al. (2009) reported similar findings, with reduced SICI (and reduced MEP amplitude) in SPMS patients relative to RRMS patients and healthy controls, and a significant correlation between EDSS and MEP amplitude, CMCT, MT and SICI (but not MRI lesion load).

It would be reasonable to suggest that the progressive disability associated with SPMS is a result of cerebral and particularly cortical degeneration rather than inflammatory demyelination, and that the former pathological process is better reflected in functional measures such as PPTMS whereas the latter is easier to characterise with radiological changes.

1.15. TMS in the assessment of disease severity and prognosis

TMS has been compared to clinical findings in an attempt to determine a correlation with disability and disease severity. Kalkers et al. (2007) reported a correlation between CMCT and clinical assessment of leg (but not hand) function, as well as EDSS, in patients with RRMS and SPMS (but not PPMS). Similar findings were reported by Kidd et al. (1998 ), supporting the idea that CMCT from leg muscles may be more robustly associated with EDSS than that of upper limb muscles.

Prognostication in MS remains challenging, with both MRI and clinical parameters having limited accuracy in predicting clinical course; measurement of CMCT has therefore been evaluated in this regard. Feuillet et al. (2007 ) performed a 6-month longitudinal study of 15 patients with early RRMS (mean EDSS 2.0) and reported a positive correlation between MEP abnormalities at baseline (either prolonged CMCT or increased MEP amplitude ratio) and disability (EDSS) at 6 months, with a robust association between 6-month motor function score and number of TMS abnormalities at baseline. Other authors have suggested that amplitude ratio may be more sensitive than CMCT, both in CIS ( Rico et al., 2009 )and clinically definite MS ( Gagliardo et al., 2007 ) patients.

Various studies have evaluated the predictive value of CMCT in conjunction with other variables. Bejarano et al. (2011) evaluated CMCT among other prognostic markers in a prospective cohort and reported that while baseline EDSS, grey matter volume and CMCT were each weakly correlated with clinical progression, the combination of these three variables in a mathematical model had a reasonable accuracy (80%) for predicting EDSS change over 2 years. Along similar lines, Fuhr (2001 ) prospectively evaluated 30 patients with RRMS or SPMS longitudinally over 2 years and demonstrated a robust correlation between EDSS score and MEP latencies as well as EDSS score and the number of abnormal evoked potentials, with a more robust correlation when a formula was applied which combined both EP scores. Leocani et al. (2006 ) multimodal evoked potential score comprising MEP and SSEP in a longitudinal study demonstrated a significant positive correlation between baseline combined evoked potential score and likelihood of disease progression over time. More recently, a composite score derived from MEP and VEP latencies has been shown in a prospective study to be predictive of disability over a 20-year follow-up period in a group of patients with RRMS and SPMS (Schlaeger et al, 2012 and Schlaeger et al, 2014). The relationship between prognosis and MRI is weaker for PPMS than RRMS ( Nijeholt et al., 1998 ) and in this group of patients a multimodal evoked potential score encompassing VEP, SSEP and MEP was shown to be predictive of disability over a 3-year period ( Schlaeger et al., 2014 ).

The timing of measurements relative to clinical relapse appears to be important; specifically, measurements made during a stable, relapse-free interval have much better prognostic value than those made during a relapse ( Schlaeger et al., 2014 ) (which can itself produce transient alterations in cortical excitability, CMCT and other parameters) ( Caramia et al., 2004 ). Caramia et al. (2004) studied a group of 79 treatment-naïve RRMS patients (EDSS 0–3) who were either in remission or in the midst of a clinical relapse, and reported a marked reduction in SICI for relapsing patients compared to stable patients or healthy controls, but with normalisation of SICI as they entered clinical remission. Relapsing patients also showed increased threshold and reduced cortical silent period, but CMCT was not significantly different between the groups. The potential implications of this are open to interpretation. It appears that clinical relapses are associated with a degree of cortical hyperexcitability at the synaptic level as demonstrated by a reduction in SICI, but also a reduction in neuronal membrane excitability as evidenced by the increased MT. These findings could reflect alterations in GABAergic inhibitory transmission or glutamatergic excitatory neurotransmission. Pathophysiologically, a relapse would be associated with tissue damage and oedema which might result in conduction block; however it could also be associated with excitotoxicity and enhanced glutamatergic transmission. TMS is ideally placed to interrogate the cerebral cortex in a functional manner and this information can then by correlated with structural imaging and biomarker data to better understand the complex interplay between these factors in the generation of MS-related disability ( Rossi et al., 2011 ).

1.16. TMS in longitudinal disease assessment

The potential use of CMCT as an objective tool for monitoring disease progression and responses to therapy has also been evaluated, with mixed results. Kandler et al. (1991) studied a cohort of 100 patients with MS and demonstrated a robust correlation between CMCT and degree of motor dysfunction according to the Kurtzke scale of pyramidal dysfunction. A subgroup of 11 clinically stable patients were re-examined over the following 3 months, and a further 27 patients who suffered a clinical relapse were examined during and after steroid treatment. Despite small numbers, there was a statistically significant correlation between clinical findings and CMCT, in that patients who clinically responded to steroid treatment had a robust reduction in CMCT and non-improvers had no change; results from stable patients were unchanged across two readings ( Kandler et al., 1991 ). Similar degrees of improvement in CMCT have also been documented with clinical improvement in response to physiotherapy ( Kandler, 1990 ) and in patients who improve without treatment for a relapse ( Sahota et al., 2005 ), making a specific effect of corticosteroids on neural excitability less likely. VEP latencies have been reported both to improve ( Brusa et al., 2001 ) and to remain static (Compston et al, 1987 and de Weerd and Jonkman, 1982) in patients who have improved clinically; SSEP latencies have not been shown to change longitudinally( de Weerd, 1987 ; Iragui et al., 1986 ; La Mantia et al., 1994 ; Smith et al., 1986 ) in patients who have improved clinically, with or without steroid therapy. Kidd et al. (1998) studied a group of 20 patients with progressive MS longitudinally and demonstrated that clinical progression over the course of 1 year was seldom associated with progressive prolongation in CMCT, unless there were also new spinal cord lesions which developed over the same timeframe.

The EDSS which is used as standard in clinical trials of new MS therapies has a number of limitations, including limited inter- and intra-rater reliability ( Hobart et al., 2000 ), as well as a strong focus on ambulation and a relative neglect of symptoms such as fatigue, cognition and upper limb dysfunction which may be equally disabling but are somewhat harder to evaluate. Furthermore, EDSS scores cannot reliably differentiate between RRMS and SPMS, nor are they always an accurate measure of accumulating disability in the context of progressive disease where patients may decline significantly while remaining within the same EDSS step. TMS has been proposed as a potential surrogate endpoint, with the principal advantage of objectivity. Reproducibility is estimated to be >90% in healthy controls, ( Hammond et al., 1987 ; Shaw and Synek, 1987 ), although may be less in patients with MS (de Weerd, 1987 and Aminoff et al, 1984). It has not been reliably established how reproducible MEP latencies are in this population, particularly over a longitudinal period, nor has it been quantified how much improvement (or indeed deterioration) on serial measurements is clinically significant.

MEP and CMCT have the advantage over VEP and non-contrast MRI that they typically parallel clinical changes ( Comi et al., 1999; Matthews and Small, 1979 ) and can show improvement as well as deterioration. Furthermore, abnormalities can be seen in all stages and phases of the disease.

1.17. Evaluation of MS treatments using TMS

1.17.1. Symptomatic therapies

TMS also has potential uses in studying the effects of various drugs on the brain function ( Ziemann, 2004 ), including symptomatic or disease-modifying treatments for MS. One such drug is 4-aminopyridine, a potassium channel blocker whose modified-release form (fampridine-MR) is licensed for the symptomatic treatment of walking disability in patients with MS ( Goodman et al., 2009 ), with some uncertainty regarding its precise mode of action. TMS has been used to interrogate this further. Fujihara and Miyoshi (1998 ) used TMS to measure upper and lower limb MEP's in six stable MS patients with bilateral leg weakness before and after intravenous 4-aminopyridine therapy. All MS patients had reduced or absent MEP responses. They demonstrated an increase in mean MEP amplitude following treatment, both in the affected upper and lower limbs and in clinically unaffected upper limbs, with no effect on MEP latency. The use of TMS in this case allowed some conclusions to be drawn regarding the mechanism of drug action, which may reflect a synchronisation of upper motor neuronal transmission in response to the drug. Another study using the closely related compound 3,4-diaminopyridine reported no change in MEP amplitude or latency but did identify changes in cortical excitability, with decrease in intracortical inhibition and increased intracortical facilitation in a paired-pulse TMS paradigm ( Mainero et al., 2004 ). The third group ( Sheean et al., 1998 ) however did not report any effect of 3,4-diaminopyridine on either MEP amplitude or resting motor threshold, although this group did not examine ICF and ICI.

Baclofen is a drug which is frequently used in the symptomatic treatment of MS-related spasticity and increased muscle tone. A single report in a patient with MS suggested some effect on the cortical silent period ( Stetkarova and Kofler, 2013 ) and various studies on healthy controls have shown no effect on SICI ( Ziemann et al., 1998 ) or on the cortical silent period. The effects of baclofen on other TMS parameters remain unknown.

Intravenous methylprednisolone has been reported to reduce SICI and increase ICF, with evidence of these alterations in cortical excitability being present as early as 3 days after treatment initiation ( Ayache et al., 2014 ). Interestingly the alterations in TMS parameters did not push treated patients closer towards those of healthy subjects, suggesting that the steroid treatment may have acted to promote neural repair mechanisms rather than restoring normal conditions of cortical excitability. Fierro et al. (2002 ) studied 24 patients with clinical relapse requiring intravenous methylprednisolone at regular or high doses and demonstrated a dose-dependant improvement in resting motor threshold and CMCT which correlated with clinical findings. An earlier study ( Salle et al., 1992 ) also supported this, showing also suggested an improvement in MEP latency in response to intravenous corticosteroids in a single-pulse TMS paradigm.

TMS can also be used in the study of experimental MS therapies, and can be a useful objective marker alongside clinical measurements. Creange et al. (2013 ) studied four patients with SPMS in a feasibility study and assessed the clinical and neurophysiological response to iron depletion (induced by blood-letting and use of recombinant human erythropoietin). Although no objective clinical improvement was identified, there were trends towards improvements in fatigue and walking, and (despite the small number of patients) significant changes in various neurophysiological parameters, including an increase in cortical excitability as indicated by decreased motor threshold and an enhancement of intracortical facilitation and cerebellothalamocortical inhibition. The significance of these findings is unclear but this small study illustrates the potential utility of TMS as a surrogate marker.

1.17.2. Disease-modifying treatments

A number of small, uncontrolled studies have explored the effects of disease-modifying treatments on TMS parameters. Feuillet et al. (2007 ) reported a normalisation of CMCT and amplitude ratio in stable interferon β1a-treated patients over a 6-month period. Another group ( White and Petajan, 2004 ) reported a change in recovery of MEP amplitude after fatiguing exercise in a group of patients being established on interferon β1a. It has been suggested that Natalizumab may improve VEP and SSEP latencies but has no effect on MEP results in a single-pulse TMS paradigm ( Meuth et al., 2011 ). Landi et al. (2015 ) reported that Fingolimod modulated cortical excitability and reduced intracortical facilitation after 60 days of treatment in a group of RRMS patients. Whether this could be explained by the anti-inflammatory effects of the medication or perhaps a direct drug effect on cortical excitability is unclear. No other published data exist regarding the effects of standard disease-modifying therapies on TMS parameters in humans with MS.

1.18. Other potential application of TMS

TMS techniques possess a unique ability to interrogate cortico-neuronal interactions and can therefore be used in the study of cortical dysfunction related to MS. A number of authors have used this technique in the study of fatigue, a common and disabling MS symptom whose pathophysiological origin remains incompletely understood.

Sheean et al. (1997 ) studied 21 MS patients with disabling fatigue using a paired-pulse paradigm but did not find any significant differences between patients and healthy controls. Liepert et al. (2005) studied a small group of MS patients with and without fatigue using TMS to study cortical excitability before and after a fatiguing motor task. Patients with fatigue had reduced SICI compared to non-fatigued MS patients, and the MT took longer to normalise following the task in fatigued patients compared to non-fatigued patients and healthy controls, regardless of disability as measured by EDSS. Scheidegger et al. (2012 ) used TMS in combination with peripheral nerve stimulation at two sites (the “triple stimulation technique”) to interrogate cortical function during a fatiguing motor task and reported significant differences between fatigued MS patients and controls, with a less than normal decline in corticospinal output seen in the MS patients after fatiguing exercise in part possibly related to impaired intracortical inhibitory mechanisms. These findings require further validation in larger groups but do lend support to the idea that MS-related fatigue may have a cortical origin.

Limited attempts have been made to correlate neurophysiological markers as measured by TMS with other biomarkers, but a small number of studies have provided interesting data. Rossi et al. (2012 ) demonstrated a positive correlation between levels of the proinflammatory cytokine interleukin 1B in the CSF and the degree of ICF observed in these patients. The clinical significance of this is unclear but this study serves to illustrate another potential use of this technology.

2. Conclusion

TMS is not a widely used tool in current clinical practice in MS, however it does have the potential to provide complementary information regarding the motor system which may have uses in diagnosis, stratification, prognostication and perhaps in monitoring response to therapy. It may enhance our understanding of the pathophysiological processes at play during both the inflammatory and progressive stages of the disease. It also has potential uses as an objective tool (in combination with clinical and radiological measures) in the evaluation of new disease-modifying therapies as well as symptomatic therapies for fatigue, gait disturbance and spasticity. Furthermore, it is safe, non-invasive and well-tolerated in the majority of patients and has very few contraindications to use. At present, TMS does not have sufficient supportive data to recommend it as a useful tool by itself, but it may well have a role in combination with clinical, radiological and biomarker information in the diagnosis or prognostication of MS and warrants further study.

Acknowledgements

Dr Marion Simpson's research is funded by a scholarship from the NHMRC (reference number APP1056294).

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Footnotes

Department of Neurology, Austin Health and Faculty of Medicine, The University of Melbourne, Melbourne, Vic, Australia

Correspondence to: Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia. Fax: +61394964065.


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