The 4th IEEE International Conference on E-Health and Bioengineering - EHB 2013 Grigore T Popa University o{Medicine and Pharmacy, ia:ji, Romania, November 21-23,2013

Modifications of Electrophysiological Parameters in

Patients with Multiple Sclerosis Orest Bolbocean

l, Bogdan Ignat

l, Cristina Grosu

l, Daniela Matei

2, Drago� Popescu

3, Cristian Dinu Popescu

l

lUniversity of Medicine and Pharmacy "Grigore T. Popa" Iasi, Romania, Faculty of General Medicine, Department of Neurology

2University of Medicine and Pharmacy "Grigore T. Popa" Iasi, Romania, Faculty of Biomedical Engineering, Department of Biomedical Sciences

3University of Medicine and Pharmacy "Grigore T. Popa" [asi, Romania, Faculty of General Medicine,

Department of Anatomy

Abstract-Multiple sclerosis (MS) is the most frequent

disabling disease of the young adult. Progression of the disease

must be documented in order to properly conduct the treatment.

Transcranial magnetical stirn ulation is able to assess the function of the motor system. Corpus callosum lesions are relatively specific and frequent in MS. As transcallosal

inhibition (TJ) is able to evaluate interhemispheric interactions,

it might be useful in assessing cortico-spinal function in MS

patients. We have evaluated the central motor conduction time

(CMCT), transcallosal inhibition latency (L TJ) and duration

(DTl) in 40 patients with MS and 18 healthy subjects. Both LTi

and DTi showed significant changes in MS patients,

proportionate to the degree of clinical impairment. DTi was

more sensitive in detecting motor pathway pathology than

CMCT (increased CMCT in 80% of patients while DTJ was

increased in 92.5% of patients). Analysis of TI is a useful and

sensitive tool in evaluating motor involvement in MS.

Keywords-TMS, transcallosal inhibition, multiple sclerosis, motor disfunction.

I. [NTRODUCTION

Multiple sclerosis (MS) is a chronic disorder of the central nervous system and is a major cause of permanent disability in young adults [1]. MS is considered to be a result of immunological, genetic, and environmental factors, including viral infection [1]. MS is characterized by multiple patches of demyelination in the brain and spinal cord. Two major forms of MS have been reported: relapsing-remitting MS (RRMS), which is the most frequent, and primary progressive MS (PPMS) [2].

Current available therapies impact on the disease evolution by reducing the number of clinical relapses, and also by diminishing MR[ activity. Quantification of disease progression is an important aspect of clinical and paraclinical follow-up of these patients and allows proper therapeutical approach - newer and more reliable types of investigations have been proposed, either imagistic or functional.

Transcranial magnetic stimulation (TMS) represents a non­invasive technique able to assess or modulate cortical excitability. [n multiple sclerosis patients TMS is used to

measure motor evoked potentials abnormalities. The most important parameter is central motor conduction time (CMCT).

Corpus callosum (CC) is an interhemispheric connection that transfers sensory, cognitive and motor information and plays a role in coordinating skilled motor functions. According to imaging studies, demyelinating lesions in corpum callosum were found in 93% of multiple sclerosis patients [3]. TMS allows functional analysis of interhemispheric motor transmission mediated via the transcallosal pathway.

The aim of our study was to determine frequency of motor and transcallosal conduction abnormalities in MS patients and also which of the parameters of transcallosal inhibition (TI) are changed, and to determine if TI investigation increases the sensitivity of TMS in detecting central conduction deficits in MS patients. We investigated 40 MS patients and 18 healthy volunteers.

II. MATERIALS AND METHOD

This trial was conducted on 58 subjects: 40 patients with multiple sclerosis (mean age 37.62 ± 9.46 years) and 18 healthy volunteers (mean age 32.2 ± 3. [ years). The clinical form of MS was: clinically isolated syndrome (C[S) in 4 subjects (10%), relapsing-remitting MS (RRMS) in 32 subjects (80%) and primary progressive MS (SPMS) in 4 subjects (10%).

The mean value of the EDSS was 2.4 ± 2.4 with values between 0.5 and 8.5. Depending on the pyramidal lesions objectified by the EDSS the patients were divided into the following groups: 17 patients (42,5%) with EDSS 1, 18 patients (45%) with EDSS 2-3 and 5 patients ([2,5% ) with EDSS 4-5.

A. Electrophysiological methods

Transcranial magnetic stimulation was performed with a Magstim Rapid® device (Magstim Co. Ltd, Whitland, Dyfed, UK) connected to a butterfly shaped coil with a diameter of 7.0 cm, able to generate a magnetic field of up to l.2 Tesla.

978-1-4799-2373-1/13/$31.00 ©2013 IEEE

To assess motor response the coil was placed in the optimal position, over the cerebral motor area. The motor evoked potential (MEP) was collected in the abductor digiti minimi muscle with surface electrodes. Facilitation was used in case of impossibility to obtain an EMG response.

To assess transcallosal inhibition, on the background of a tonic contraction of the ipsilateral muscle we have performed stimulation of the same cerebral hemisphere, with an intensity of 120% of the motor threshold, causing inhibition of the EMG signal appearance, but without the occurrence of MEP. There have been four successive stimulations at an interval of 10 seconds, the ipsilateral muscle contraction force being of 50 % of the maximum voluntary contraction.

The latency of the transcallosal inhibition (L TI) was measured between the magnetic stimulation artifact and the moment when the visible tonic EMG activity fell below the mean EMG amplitude before transcranial stimulation.

The duration of the transcallosal inhibition (DTI) was calculated from the beginning of the TI until the moment when the EMG amplitude reached its median values before the transcranial stimulation. We have measured the CMCT, LTI and DTI in all subjects.

B. Statistical methods

The statistical analysis of the results was performed using

the software package ST A T1STlC A 6.0 (StatSoft Inc., USA).

The values are presented as mean values and standard

deviation (M ± s). The values were considered statistically

significant at the 5% level (p < 0.05).

III. RESULTS

In patients with multiple sclerosis, the CMCT for left hemisphere was 10.44 ± 6.44 ms vs 8.04 ± 0.63 ms in normal volunteers with p<0.03, Table I. For right hemisphere CMCT was 10.81 ± 5.05 ms in MS vs 8.04 ± 0.81 ms for controls with statistical significance p<0.03 (Fig. 1 ). Increases in central motor conduction time have been objectified in 80% of patients with MS.

TABLE I

MOTOR EVOKED POTENTIAL V ALVES TMS

Volunteers MS patients P parameters

CMCT Left 8.04 ± 0.63 10.44 ± 6.44 0.03 hemisphere Right 8.04±0.81 10.81 ± 5.05 0.03 hemisphere

LTI Left 38.83 ± 4.83 38.51 ± 4.13 0.18 hemisphere Right 33.23 ± 4.73 39.32±4.13 0.02 hemisphere

DTI Left 3l.64 ± 4.85 36.21 ± 5.97 0.049 hemisphere Right 32.19±6.27 41.37 ± 6.93 0.003 hemisphere

L TI were significantly increased in MS patients compared to healthy volunteers only for right hemisphere (39.32 ± 4.13 ms vs 33.23 ± 4.73 ms with p<0.02).

ms C@ntral motor conduction time 12.00 ...-----------

10.00 +---'-="""---

8.00

6.00

4.00

2.00

0.00 Controls MS

Left Hemisphere

Ri ght Hemisphere

Fig. I. Central motor conduction time in groups study

ms Latency of the transcallosal inhibition

40 ,----------38 +------

36 +------34 +------

32

30 Controls MS

• Left hemisphere

• Right hemisphere

Fig. 2. Latency of the transcallosal inhibition in groups study

ms

50

40

30

20

10

0

Latency and duration of the transcalossal inhibition

• Controls

• MS -EDSS1

• MS-EDSS2-3

• MS-EDSS4-5

LTI OTI

Fig. 3. Latency and duration of the transcalossal inhibition in groups study

The increase of the latency transcallosal inhibition was found in 31 of the 40 patients (77.5%) of subjects with MS examined. Unilateral or bilateral changes in the duration was recorded in 92.5% of patients with MS (Fig.2).

In patients with mild impairment of the cortico-spinal tract (EDSS - I) compared to the control group we did not find a statistically significant increase of the transcallosal inhibition latency (35.64 ± 13.18 ms vs 3l.67 ± 7.24 ms, p<0.48) (Table II).

In patients with slight (EDSS 2-3) and severe impairment of the cortico-spinal tract (EDSS 4-5) the latency of the transcallosal inhibition were much increase compared to the control group (EDSS 2-3: 44.27 ± 18.83 ms vs 31.67 ± 7.24,

p<0.0025; EDSS 4-5: 38.88 ± 8.44 ms vs 31.67 ± 7.24, p<0.0024).

The duration of transcallosal inhibition were modified compared to the control group, with high statistical significance as follows: (EDSS I: 37.32 ± 16.18 ms vs 31.43 ± 6.88, p<0.008; EDSS 2-3: 41.00 ± 13.64 ms vs 31.43 ± 6.88, p<0.002; EDSS 4-5: 48.28 ± 12.58 vs 31.43 ± 6.88, p<0.002) (Fig.3).

In patients with mild impairment of the cortico-spinal tract (EDSS - 1) the L TI we did not find a statistically significant increase, whereas DTI presented statistically significant changes.

In patients with slight and severe impairment of the cortico­spinal tract (EDSS 2-5) both the latency and the duration of transcallosal inhibition were modified compared to the control group, with high statistical significance (Table II).

Parameters Volunteers Piramyda1

EOSS 1 Piramydal EDSS 2-3 Piramydal EOSS 4-5

TABLE II

TRANSCALLOSAL INHIBITION VALUES LTI P DTI

31.67 ± 7.24 NS 31.43 ± 6.88

35.64 ± 13.18 0.48 37.32 ± 16.18

44.27 ± 18.83 0.0025 41.00 ± 13.64

38.88 ± 8.44 0.0024 48.28 ± 12.58

IV. DISCUSSIONS

P NS

0.008

0.002

0.002

Prediction of long-term disability in MS patients is

essential. Corpus callosum index is a parameter commonly

used to identify changes in brain volume. Research conducted

by Yaldizli O. et al. (20 I 0) on a group of 165 patients with

MS showed a significant degree of atrophy of the corpus

callosum in these patients [4]. Atrophy increased with the

disease progression by about 1.3% per year. In patients with

secondary progressive form, corpus callosum atrophy was

double compared to subjects with relapsing-remitting form .

Also there was an increasing trend of CC atrophy in patients

who were not under immunomodulatory treatment compared

with those receiving medication.

Magnetic resonance investigations have limitations in

terms of detection and quantification of the degreee of

destruction in the nervous system. Nucifora et al. (2007)

conducted a study on the microstructure and brain

connections using DTI technology (diffusion tensor imaging)

[5]. Thus, patients with multiple sclerosis showed a high

diffusivity and a decrease in fractional anisotropy in areas of

demyelination in the corpus callosum, which demonstrates

destruction of microstructural white matter at this level.

A tractography study conducted by Lin et al. (2007) in MS

patients with apparently intact white matter showed an

abnormal diffusion in the pyramidal tract [6].

Even if MRI examination of brain volume has a valuable

predictive value, sophisticated MRI techniques are often

inaccessible in current clinical practice.

Transcranial magnetic stimulation method allows the

functional assessment of the disease impact on the pyramidal

tract, unlike the imagistic investigations that quantify only the

presence or absence of lesions (structural information).

Central motor conduction time is a parameter used to quantify

specific nerve transmission in the brain and spinal pyramidal

tract and also to highlight possible malfunctions at this level.

It is probably the most accurate marker of abnormal

transmission in the upper pyramidal tract [7], [8] and is the

current standard in TM D for MS patients.

There is a positive relationship between corpus callosum

atrophy and the intensity of symptoms in multiple sclerosis

patients [9]. 96 % of patients with severe atrophy of the

corpus callosum showed moderate to severe clinical

symptoms, while 78 % of the patients without signs of

damage in this region had slight or no clinical symptoms.

The area of the corpus callosum lesions present on

midsagittal MRI image has been found to positively correlate

with increased latency and duration of transcallosal inhibition

in MS patients [10].

Evaluation of the duration of transcallosal inhibition was

more sensitive for the detection of pathological changes in

patients with multiple sclerosis compared to analysis of

central motor conduction time abnormalities.

Increases in latency on transcallosal inhibition were

recorded in 77.5 % of cases. D ifferences were statistically

significant (p = 0.02), but if analysis was performed

separatelly for each hemisphere, changes reached statistical

significance only on the right side.

Increases in the duration of Tl were recorded in 92.5 % of

cases, compared to 80 % of patients with changes in CMCT.

Thus, 13 % of the pyramidal tract anomalies were to be

omitted if the determination of transcallosal inhibition would

not have been done.

These changes in duration of TI were statistically

significant bilaterally, and are better expressed on the right

side - it can be an expression of the higher excitability of the

dominant motor cortex in right handed persons.

Increasing the duration of TI, without changes in TI latency

can be due to occurrence of a small number of demyelinated

fibers in the corpus callosum. Pulse propagation along intact

fibers with large diameter may explain normal or slightly

modified TI latency. Pulse propagation through small

diameter fibers results in a dispersion of neuronal

transmission flow directed to the contralateral hemisphere, a

phenomenon that leads to growth in the duration of the TI.

Transcallosal inhibition parameters that were analyzed in

the groups of MS subjects showed increased values consistent

with the clinical degree of pyramidal impairment.

The duration of transcallosal inhibition values increased

significantly in patients with severe pyramidal clinical

impairment compared to subjects with mild pyramidal

deficits.

The frequent occurrence of TI abnormalities compared with

CMCT changes in MS patients may be explained by the

frequent presence of degenerative lesions in the corpus

callosum in patients with multiple sclerosis[4], [ I I], which

can lead to its atrophy even in early stages [12], [13], [14].

Similar results were found by other authors [15], [16].

V. CONCLUSIONS

Transcallosal inhibition parameters were altered in patients

with multiple sclerosis and there is a positive correlation

between the degree of clinical impairment and pathological

changes of transcallosal transmission. The incidence of TI parameters changes is higher than

those of the CMCT, showing significant involvement of the corpus callosum in the disease process.

Duration of the transcallosal inhibition is a very sensitive marker in assessing transcallosal inhibition abnormalities in MS patients. Analysis of transcallosal inhibition must be part of the TMS examination in MS patients, and can increase its

sensitivity in detecting motor system abnormalities.

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