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Ipsilateral silent period: A marker of callosal conduction abnormality in early relapsing–remitting multiple sclerosis?
Journal of the Neurological Sciences 250 (2006) 133 – 139 www.elsevier.com/locate/jns
Ipsilateral silent period: A marker of callosal conduction abnormality in early relapsing–remitting multiple sclerosis? Patrick Jung a , Astrid Beyerle a , Marek Humpich a , Tobias Neumann-Haefelin a , Heinrich Lanfermann b , Ulf Ziemann a,⁎ a
Department of Neurology, Johann Wolfgang Goethe-University, Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany b Institute of Neuroradiology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany Received 8 May 2006; received in revised form 16 August 2006; accepted 16 August 2006 Available online 2 October 2006
Abstract Objective: The corpus callosum (CC) is commonly affected in multiple sclerosis (MS). The ipsilateral silent period (iSP) is a putative electrophysiological marker of callosal demyelination. The purpose of this study was to re-assess, under recently established optimised protocol conditions [Jung P., Ziemann U. Differences of the ipsilateral silent period in small hand muscles. Muscle Nerve in press.], its diagnostic sensitivity in MS, about which conflicting results were reported in previous studies. Methods: ISP measurements (onset, duration, and depth) were obtained in the abductor pollicis brevis (APB) muscle of either hand in 49 patients with early relapsing–remitting MS (RRMS) (mean EDSS, 1.3). Standard central motor conduction times to the APB (CMCTAPB) and tibial anterior muscles (CMCTTA), and magnetic resonance images (MRI) were also obtained. Results: ISP measurements showed a similar diagnostic sensitivity (28.6%) as CMCTAPB (24.5%), while diagnostic sensitivities of CMCTTA (69.4%) and MRI of the CC (78.6%) were much higher. Prolongation of iSP duration was the most sensitive single iSP measure. ISP prolongation occurred more frequently when CMCTAPB to the same hand was also prolonged (40.0% vs. 8.4%, p b 0.0001). The correlation between iSP duration and CMCTAPB was significant (Pearson's r = 0.24, p b 0.02), suggesting that iSP duration can be contaminated by demyelination of the contralateral corticospinal tract. ISP duration did not correlate with MRI abnormalities of the CC. Conclusions: ISP measures are neither a sensitive nor a specific marker of callosal conduction abnormality in early RRMS. © 2006 Elsevier B.V. All rights reserved. Keywords: Ipsilateral silent period; Central motor conduction time; Transcranial magnetic stimulation; Corpus callosum; Relapsing–remitting multiple sclerosis
1. Introduction Focal lesions and atrophy of the corpus callosum (CC) are common in multiple sclerosis (MS) [2–4]. A postmortem analysis of MS patients with long disease duration demonstrated a reduction of N 50% in the total number of transcallosal axons compared to controls who died of non-neurological diseases [5]. Already in clinically early MS, diffuse axonal loss and brain atrophy are present to a significant extent [6,7]. Accordingly, MRI morphometry showed CC atrophy at an early stage of MS [8]. These structural changes of the CC in ⁎ Corresponding author. Tel.: +49 69 6301 5739; fax: +49 69 6301 6842. E-mail address: [email protected] (U. Ziemann). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.08.008
early MS seem to be accompanied by interhemispheric dysfunction as revealed by neuropsychological tests such as dichotic listening, crossed tactile finger localization and alternate finger tapping [9–11], and by electrophysiological measurements, in particular the ipsilateral silent period (iSP) [12– 15]. The iSP is elicited by focal transcranial magnetic stimulation (TMS) of one primary motor cortex (MI), and refers to the suppression of voluntary activity in the electromyogram (EMG) of a contracting ipsilateral hand muscle [16– 18]. ISP testing is a simple and little time consuming noninvasive technique that is thought to assess the function of transcallosal fibres mediating the inhibitory effect from the stimulated to the non-stimulated voluntarily active MI of the opposite hemisphere [17,18]. The iSP can be analysed
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according to onset latency, duration, depth and the transcallosal conduction time (TCT). Several studies showed abnormal iSP measures in MS [12–14], but the details of the reported results are rather conflicting. Any of these studies found a different iSP measure to be the most sensitive abnormality (TCT [12]; iSP onset latency [13]; iSP duration [14]). In addition, the reported diagnostic sensitivities of iSP measurements showed large variation, ranging from 80% in early RRMS [14] and 74% in a mixed sample of RRMS and chronic progressive MS [13] to 46% in a mixed sample of RRMS and secondary progressive MS [12]. In contrast, TMS measurements of central motor conduction time (CMCT) are now a diagnostic standard to assess the integrity of the corticospinal tract in patients with definite MS, and many studies reported consistently diagnostic sensitivities between 60% and 80% for both upper and lower limbs [19–22]. The primary aim of this study was to clarify the diagnostic sensitivity of the iSP in identifying abnormalities of callosal conduction in a strictly defined group of patients with clinically early RRMS, using a recently optimised iSP recording protocol [1]. In addition, the relations between iSP and CMCT, and between iSP and morphometric brain MRI measurements, especially of the CC, were examined. 2. Materials and methods 2.1. Subjects and patients Forty-nine patients (22 men and 27 women; aged 23 to 54 years; mean age ± S.D., 35.2 ± 7.6 years) and 20 healthy controls (13 men and 7 women, aged 18 to 44 years; mean age ± S.D. = 29.0 ± 6.6 years) were included in this study, which was approved by the local ethics committee. All patients and controls gave their written informed consent. The healthy subjects were paid for participation. According to the current diagnostic criteria for MS [23], 40 patients were classified as having definite RRMS and 9 patients as having possible MS. In agreement with the MS therapy consensus group [24], all patients with possible MS were recommended to start an immunomodulatory therapy with interferon-beta or glatirameracetate due to positive oligoclonal IgG in the CSF and more than 6 T2 lesions on cranial MRI. Diagnosis had been established 0.9 ± 1.5 years (mean ± S.D.) prior to this study. All patients were investigated (physical examination and electrophysiological measurements) at least 6 weeks after their last relapse in a clinically stable phase. The expanded disability status scale (EDSS) [25] ranged from 0.0 to 4.0 (median = 1.5; mean ± S.D. = 1.3 ± 1.0). 2.2. TMS measures ISP onset latency, iSP duration, iSP depth and TCT were measured in the abductor pollicis brevis (APB) muscle of either hand. Muscle activity was recorded by surface EMG, using Ag–AgCl cup electrodes in a belly–tendon montage. The EMG was amplified, bandpass filtered (0.01–2 kHz)
and digitised (sampling rate, 5.12 kHz, Neuroscreen, Jaeger– Toennies, Höchberg, Germany). Focal TMS was applied to the left or right MI with a figure-of-eight coil (outer diameter of each wing, 90 mm) connected to a Magstim 200 magnetic stimulator (The Magstim Company, Whitland, UK) during maximal voluntary isometric contraction of the ipsilateral APB. These contractions were performed by abduction of the thumb against a rigid manipulandum while the wrist was firmly stabilized by Velcro straps. The coil was held tangential to the scalp. The optimal stimulation site was defined as the coil location that produced consistently largest MEP amplitudes in the contralateral APB. This stimulation site was used for the iSP measurements because it was shown previously that the motor cortical topography of the contralateral MEP and the iSP correspond closely [16,26]. The coil handle pointed backwards, and the angle between the midsagittal plane and the coil handle was approximately 0°, 22.5°, or 45°, according to the individually determined angle that resulted in the longest iSP. The stimulus intensity was set to 80% of maximal stimulator output (MSO). This intensity was selected because it produces stable plateau values for iSP onset latency and iSP duration [17]. For either hand, 15 trials were recorded with a sweep window covering 60 ms prior to and 140 ms after TMS. The intertrial interval was 5–7 s. Short pauses of contraction were allowed to prevent fatigue. The level of voluntary EMG activation was played back via a loudspeaker. This protocol of iSP measurements followed a recently established optimised protocol [1]. The major advantage in comparison to previously used protocols [12–14] is the selection of the APB as the target muscle because the iSP in other small hand muscles, in particular the first dorsal interosseous, may be obscured by a second phase of inhibition that is most likely mediated by an ipsilateral corticospinal pathway rather than by the CC [1,17]. This second phase of inhibition is absent in the APB [1]. In addition, the resting motor threshold (RMT) was determined in the voluntarily relaxed APB to the nearest 1% of MSO. RMT was defined as the minimum stimulus intensity that elicited MEPs N 50 μV in at least five of ten consecutive trials [27]. For CMCT measurements, standard contralateral MEPs were recorded from the APB and tibial anterior (TA) muscles during slight isometric contraction (5%–10% of the maximal strength) using a circular magnetic coil (outside diameter, 140 mm) at a stimulus intensity of 70% MSO [27]. The current direction in the coil, when viewed from above, was counterclockwise for MEP recordings on the right side and clockwise for the left side. In addition, spinal MEPs were elicited by stimulation of cervical and lumbar spinal roots via the circular magnetic coil at a stimulus intensity of 70% MSO. The shortest onset latency of the spinal MEP was defined as the peripheral motor conduction time. CMCTs to the APB (CMCTAPB) and TA (CMCTTA) were calculated by subtracting the peripheral motor conduction time from the shortest onset latency of the cortical MEP [27].
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2.4. Data analysis and statistics
Fig. 1. Illustration of the CC segmentation procedure (modified from [28]) and determination of the pons reference area in a midsagittal T2w MR image of a patient with RRMS. For CC segmentation, the maximal length of the CC (line between the most anterior and posterior points of the CC) was quantified at first. Then perpendiculars were drawn at one-third and one-half of maximal CC length resulting in four callosal segments (CC1–4). CC1 contains the anatomic labels rostrum, genu and rostral body, CC2 corresponds to the anterior midbody, CC3 to the posterior midbody, CC4 comprises the isthmus and splenium. For evaluating the relative atrophy in the four callosal segments, a midsagittal pons reference area was determined. Towards this end, the most posterior point of the pontomedullar cistern was identified (origin of arrow). About 5 mm perpendicular and cranial from this point (arrowhead), a line was drawn orthogonal to the brainstem axis. Then, a second line paralleled this line 5 mm above in the direction of the brainstem axis. Finally, the implied pontine area was marked.
ISP onset and iSP duration were automatically and objectively measured for either hand and individual by means of a previously described graphical method [31]. ISP depth was defined in two different ways: (1) the minimum EMG level during the iSP (dISP-max); and (2) the average EMG level during the iSP (dISP). Both measures were expressed as a percentage of the mean pre-stimulus EMG in the 60 ms prior to the TMS pulse, and these values were subtracted from 100 [16]. The TCT was calculated by subtracting the shortest MEP onset latency from the iSP onset latency in the APB of the same hand. ISP measures and CMCT were considered abnormal if values lay outside the 95% confidence interval of the healthy controls (mean ± 2.5 S.D.). The upper normal limit of CMCTAPB was 9.2 ms, the maximum interside difference 2.0 ms. The upper normal limit of CMCTTA was assessed under consideration of the body length [32]. The upper normal limits of the iSP measures can be derived from Table 1. To evaluate differences of iSP measures between patients and controls, Student's two-tailed t-tests for unpaired samples were applied. Relations between clinical signs of central motor deficits and TMS measures were evaluated with χ2 tests. Spearman's rank order correlation coefficient ρ was determined to examine the relation between iSP duration and MRI measures. A p-value b0.05 was considered significant. All data are presented as means ± S.E.M., unless stated otherwise. 3. Results
2.3. MRI measures 3.1. TMS measures In 28 patients, axial fast fluid-attenuated inversion recovery (FLAIR, TE/TI/TR = 110/2358/9000 ms, flip angle 180°, slice thickness 6 mm, 230-mm field of view, 132 × 256 matrix) and sagittal T2-weighted (T2w, TE/ TR=112/5205 ms, flip angle 180°, slice thickness 3 mm, 230-mm field of view, 270 × 512 matrix) MR brain images were acquired with a 1.5-T scanner. Brain lesion number and volume were determined in both axial FLAIR (supratentorial lesions) and sagittal T2w (brainstem and cerebellar lesions) images. Midsagittal T2w MR images were aligned to the anterior commissure (AC)–posterior commissure (PC) plane. The CC was then segmented into 4 subregions (CC1–4, Fig. 1), similar to a previously described method [28]. The CC volume (ml) was computed by summation of the CC area (mm2) in 4 adjacent T2w sagittal slices in which the CC could be clearly differentiated from the cingulate gyrus, and by multiplication of the resultant area with the section interval (3.3 mm)/1000. Relative CC atrophy was defined as the percentage of the midsagittal CC area compared to a midsagittal pons reference area (Fig. 1). This reference area was chosen because the pons, in contrast to the CC, is relatively little affected in RRMS by local tissue damage and regional atrophy [29,30].
There were no differences in RMT between RRMS patients and healthy controls (right APB, 39.3 ± 1.1% MSO vs. 39.1 ± 1.1% MSO, respectively; left APB, 39.7 ± 1.2% MSO vs. 40.3 ± 1.4% MSO, respectively). Since stimulus Table 1 Comparison of iSP measures between healthy control subjects (n = 20) and patients with early RRMS (n = 49) Measure
Controls Patients Points with (mean ± S.D.) (mean ± S.D.) abnormal measure (%)
iSP onset latency (ms) iSP duration (ms) TCT (ms) dISP-max (%) dISP (%) Side difference: iSP onset latency (ms) Side difference: iSP duration (ms) Side difference: TCT (ms)
35.6 ± 4.3
34.9 ± 4.7
4.1
26.4 ± 5.2 15.0 ± 3.2 77.9 ± 4.9 56.0 ± 6.9 3.4 ± 2.5
32.3 ± 9.0⁎ 13.6 ± 4.2 76.1 ± 10.0 56.4 ± 9.5 3.6 ± 3.9
22.4 6.1 6.1 2.0 2.0
4.1 ± 3.0
5.8 ± 6.4
12.2
2.8 ± 2.4
3.4 ± 3.4
6.1
⁎ p b 0.01; normative limits were defined by mean ± 2.5 S.D.
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Fig. 2. Example of iSP recordings from an RRMS patient with unilateral prolongation of iSP duration in the left APB (right panel). Data are averages from 15 single-trial rectified sweeps. Horizontal lines indicate the calculated upper and lower variation limits of the pre-stimulus EMG; the resulting iSP onset and offset latencies are indicated by the vertical dashed lines.
intensity for the iSP measurements was set to 80% MSO (see methods), this is an important negative result which rules out that differences in relative stimulus intensity have accounted for the obtained differences in iSP measures between patients and controls (see below). There were also no significant differences in the level of the mean pre-stimulus EMG or the variance of the prestimulus EMG, expressed as the mean consecutive difference of successive data points in the mean pre-stimulus EMG, between RRMS patients and healthy controls (mean level: 0.31 ± 0.17 mV vs. 0.38 ± 0.27 mV, mean consecutive difference: 0.017 ± 0.008 mV vs. 0.021 ± 0.011 mV) that could have affected the comparison of iSP measures between the two groups. ISP duration was significantly longer in the RRMS patients compared to healthy controls (32.3 ± 1.2 ms vs. 26.4 ± 1.2 ms, p b 0.005), while no significant differences were detected for iSP onset latency (34.9 ± 0.6 ms vs. 35.6 ± 1.0 ms), TCT (13.6 ± 0.5 ms vs. 15.0 ± 0.7 ms), dISP-max (76.1 ± 1.8% vs. 77.9 ± 0.8%) or dISP (56.4 ± 1.6% vs. 56.0 ± 1.1%). Consequently, iSP duration was the most sensitive iSP measure (Table 1 and
Fig. 3. Numbers of RRMS patients (n = 49) with abnormalities of iSP measures (upper left circle), CMCTs to the APB (upper right circle) and CMCTs to the TA (lower circle). No abnormalities were detected in 12 patients. Only 3 patients had abnormalities exclusively in the iSP measures. Note that iSP measurements add little to the diagnostic work-up in early RRMS.
Fig. 2). Additional consideration of pathological interhemispheric differences of the iSP measures resulted in only a small increase of abnormal findings (Table 1). The combined percentage of pathological findings of all iSP measures (at least one abnormal finding in a given patient) was 28.6%. This diagnostic sensitivity was similar as for CMCTAPB (24.5%) but much lower than the one for CMCTTA (69.4%). In only 3 out of 49 patients (6.1%), iSP measures were the only abnormal finding (Fig. 3). Abnormalities in iSP occurred more frequently when CMCTAPB to the same hand was prolonged compared to when it was normal (40.0% vs. 8.4%; p b 0.0001, 98 hands). Accordingly, the iSP duration was longer when CMCTAPB to the same hand was prolonged compared to when it was normal (39.6 ± 3.8 ms vs. 31.2 ± 0.8 ms, p b 0.002, 98 hands, Fig. 4). The correlation between iSP duration and CMCTAPB to the same hand was significant but weak (Pearson's r = 0.24, p b 0.02).
Fig. 4. ISP duration (mean ± 1 S.D.) in patients with RRMS grouped according to whether CMCTAPB to the same target muscle was normal (left, nCMCT) or prolonged (right, pCMCT). Note that iSP duration was significantly longer in the group with prolonged CMCTAPB.
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3.2. Relation of TMS measures to clinical findings 51.0% of the RRMS patients had clinical central motor signs in the past or at present of at least one arm (20.4%) and/or one leg (49.0%). The percentage of abnormal CMCTAPB findings differed significantly between patients with vs. without previous or current clinical central motor signs of at least one arm (45.5% vs. 11.5%, p b 0.005, n = 98), while the percentage of abnormal iSP measures was not significantly different between these two groups (27.3% vs. 14.9%). Further, there was no significant difference of the percentage of abnormal CMCTTA between patients with vs. without clinical central motor signs of the lower limbs (73.1% vs. 56.9%). There were no significant differences in the percentage of abnormal findings for CMCTAPB, CMCTTA or iSP for patients with definite RRMS compared to those with possible RRMS. 3.3. Relation of iSP measures to MRI findings The 28 RRMS patients in whom an MRI was obtained at the time of the TMS investigations had a mean number of brain lesions of 15 ± 2, the mean total volume of brain lesions was 11.8 ± 2.5 ml. A large portion of patients (78.6%) showed at least one visible T2 lesion in the CC, and the mean number of lesions in the CC was 3 ± 1. CC lesions were mostly wedgeshaped with the extended basis pointing inferiorly. In terms of lesion volume, the CC was on average only mildly affected with a mean value of 5.6 ± 1.3% (CC1, 5.5 ± 1.3%; CC2, 7.9 ± 2.0%; CC3, 6.0 ± 1.7%; CC4, 5.0 ± 1.5%). The midsagittal area of the whole CC was 555.2 ± 15.9% of the midsagittal pons reference area (CC1, 225.4 ± 6.5%; CC2, 62.7 ± 2.1%; CC3, 55.8 ± 1.8%; CC4, 211.3 ± 7.5%). The mean size of the midsagittal pons reference area was 109.7 ± 1.9 mm2 and none of the patients showed T2 lesions in that area. Correlations between iSP duration, the most sensitive iSP measure, and brain lesion number (ρ = − 0.082), brain lesion volume (ρ = 0.038), lesion number of the whole CC and CC segments 1–4 (ρ = 0.114–0.292), percentage lesion volume of the whole CC and CC segments 1–4 (ρ = − 0.066–0.248), or relative atrophy of the whole CC and the four CC segments (ρ = − 0.075 to − 0.185) were all not significant. Moreover, none of the investigated MRI measures showed a significant difference between MS patients with a pathologically prolonged vs. normal iSP duration (Mann–Whitney U tests). The most distinct, albeit not significant, difference was detected for the relative atrophy of CC3 between the two groups, with a more pronounced relative CC3 atrophy of the patients with a prolonged vs. normal iSP (49.5 ± 3.9% vs. 57.5 ± 1.9%, p = 0.08). 4. Discussion By applying an optimised iSP recording protocol [1], we were unable to replicate the superior sensitivity of iSP measures in comparison to standard CMCT measurements found in previous studies of MS patients [13,14]. In those
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studies, iSP recordings were made in the first dorsal interosseous (FDI) muscle. We demonstrated in a study of healthy subjects that a second phase of inhibition that merges into the preceding iSP occurs frequently in the FDI but almost never in the APB [1]. Very likely, this second phase of inhibition is not mediated via the CC but rather represents inhibition along an ipsilateral corticospinal projection because it persisted at least in some patients with a complete agenesis of the CC while the iSP was always absent in these patients [17]. Therefore, it is difficult to estimate to which extent the high diagnostic sensitivity of iSP measures in the previous studies [13,14] was caused by dysfunction of the CC, or dysfunction of the putative ipsilateral corticospinal pathway, or both. Although iSP measures to the APB are not contaminated by this second phase of inhibition, and thus may assess callosal conduction abnormality more specifically, other problems exist (contamination of iSP measures by corticospinal tract demyelination, lack of correlation to MRI measures of CC lesion or CC atrophy) that will be discussed in detail in the following paragraphs. 4.1. Possible mechanisms of abnormal iSP duration It is currently thought that the iSP reflects an inhibition of voluntary corticospinal activity in the non-stimulated MI, elicited by focal TMS of the other MI and mediated through the CC [17,18]. Therefore, a prolongation of iSP duration could be explained by involvement of either the CC or the corticospinal tract that originates from the non-stimulated MI. Partial demyelination of callosal fibres will result in a normal iSP onset through normally conducting fibres but dispersed iSP transmission through demyelinated fibres. This, in turn, will lead to a delayed iSP offset. Partial demyelination of corticospinal tract fibres that originate in the non-stimulated M1 and project to the target muscle ipsilateral to the stimulated M1 will result in a normal iSP onset from interruption of voluntary activity in normally conducting fibres, but dispersed transmission of resumption of voluntary activity along demyelinated fibres. This, in turn, will also lead to a delayed iSP offset. The present data support a role for this second mechanism because iSP duration was significantly more often prolonged if CMCTAPB to the same target muscle was also abnormal (Fig. 4), and iSP duration correlated significantly with CMCTAPB. In accordance with these observations, it was previously noted that an abnormal CMCT to the FDI was always associated with abnormal iSP measures, in particular iSP duration [15]. Therefore, it is very likely that iSP duration does not assess specifically demyelination of callosal motor fibres but, in addition, demyelination of the fibres of the contralateral corticospinal tract. This conclusion gains additional support from the present finding that the TCT, which is calculated by subtraction of the shortest MEP latency from the iSP onset latency in the APB of the same hand, and therefore should address more specifically demyelination of callosal motor fibres, showed a much lower diagnostic sensitivity (6.1%) than iSP duration (22.6%).
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4.2. Relation of iSP measures to MRI findings ISP sensitivity was low (28.6%) despite macroscopically visible CC lesions on MRI in a high proportion of patients (78.6%), and there were no significant correlations between iSP duration and MRI measures of CC lesion load or CC atrophy. In addition to the problem that our data suggest that the iSP duration does not specifically address conduction abnormalities of the CC but is contaminated by demyelination of the contralateral corticospinal tract, there exist several other potential explanations for the discrepancy between iSP and MRI measures. First, iSP duration addresses demyelination, while MRI measures reflect other pathology such as inflammation (T2w lesion) or axonal degeneration (MRI measures of atrophy). This view is supported by previous studies which showed that composite evoked potential scores relate closely to clinical disability in MS [33,34] while this is the case to only a much lesser extent for MRI measures, in particular T2w lesion load [33,35]. Another explanation for the dissociation between iSP and MRI measures is that the CC was frequently but only mildly affected on T2w MRI. However, the present findings demonstrated a trend towards a higher relative atrophy specifically of the CC3 (i.e. the posterior body of the CC) in the patients with a pathologically prolonged iSP duration compared to those with a normal iSP duration. This is consistent with recent data in humans that identified the posterior body and isthmus of the CC as the site where the transcallosal fibres connecting the MI of the two hemispheres are located [18,36]. Finally, in non-human primates, there exist only few [37,38] but presumably functionally significant transcallosal fibres between homologous hand representations of MI in the two hemispheres although the total quantity of transcallosal fibres in humans is large [39]. For this reason, the stochastic probability for damage of the relatively few and short transcallosal motor fibres is low, especially in patients with early RRMS, in whom the CC lesion volume is usually small. In contrast, the corticospinal projection to the lower limbs, according to its much longer length, should have a higher risk for demyelination. In summary, it is plausible that, for these various reasons, iSP measures are not a sensitive electrophysiological marker to detect abnormal conduction across the CC in clinically early RRMS. This is supported by the present study and previous data [12]. 4.3. Significance and conclusions This study strongly suggests that the iSP does not assess specifically conduction along the corpus callosum. Conduction abnormality along the contralateral corticospinal tract may contribute to the alteration of iSP measures. This places a caveat as to the interpretation of abnormal iSP data in other studies that increasingly often use the iSP to identify callosal conduction abnormality in neurological disorders with potentially confounding involvement of the corticospinal tract [40,41]. For the reasons of unclear topographic specificity
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Ipsilateral silent period: A marker of callosal conduction abnormality in early relapsing–remitting multiple sclerosis? Patrick Jung a , Astrid Beyerle a , Marek Humpich a , Tobias Neumann-Haefelin a , Heinrich Lanfermann b , Ulf Ziemann a,⁎ a
Department of Neurology, Johann Wolfgang Goethe-University, Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany b Institute of Neuroradiology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany Received 8 May 2006; received in revised form 16 August 2006; accepted 16 August 2006 Available online 2 October 2006
Abstract Objective: The corpus callosum (CC) is commonly affected in multiple sclerosis (MS). The ipsilateral silent period (iSP) is a putative electrophysiological marker of callosal demyelination. The purpose of this study was to re-assess, under recently established optimised protocol conditions [Jung P., Ziemann U. Differences of the ipsilateral silent period in small hand muscles. Muscle Nerve in press.], its diagnostic sensitivity in MS, about which conflicting results were reported in previous studies. Methods: ISP measurements (onset, duration, and depth) were obtained in the abductor pollicis brevis (APB) muscle of either hand in 49 patients with early relapsing–remitting MS (RRMS) (mean EDSS, 1.3). Standard central motor conduction times to the APB (CMCTAPB) and tibial anterior muscles (CMCTTA), and magnetic resonance images (MRI) were also obtained. Results: ISP measurements showed a similar diagnostic sensitivity (28.6%) as CMCTAPB (24.5%), while diagnostic sensitivities of CMCTTA (69.4%) and MRI of the CC (78.6%) were much higher. Prolongation of iSP duration was the most sensitive single iSP measure. ISP prolongation occurred more frequently when CMCTAPB to the same hand was also prolonged (40.0% vs. 8.4%, p b 0.0001). The correlation between iSP duration and CMCTAPB was significant (Pearson's r = 0.24, p b 0.02), suggesting that iSP duration can be contaminated by demyelination of the contralateral corticospinal tract. ISP duration did not correlate with MRI abnormalities of the CC. Conclusions: ISP measures are neither a sensitive nor a specific marker of callosal conduction abnormality in early RRMS. © 2006 Elsevier B.V. All rights reserved. Keywords: Ipsilateral silent period; Central motor conduction time; Transcranial magnetic stimulation; Corpus callosum; Relapsing–remitting multiple sclerosis
1. Introduction Focal lesions and atrophy of the corpus callosum (CC) are common in multiple sclerosis (MS) [2–4]. A postmortem analysis of MS patients with long disease duration demonstrated a reduction of N 50% in the total number of transcallosal axons compared to controls who died of non-neurological diseases [5]. Already in clinically early MS, diffuse axonal loss and brain atrophy are present to a significant extent [6,7]. Accordingly, MRI morphometry showed CC atrophy at an early stage of MS [8]. These structural changes of the CC in ⁎ Corresponding author. Tel.: +49 69 6301 5739; fax: +49 69 6301 6842. E-mail address: [email protected] (U. Ziemann). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.08.008
early MS seem to be accompanied by interhemispheric dysfunction as revealed by neuropsychological tests such as dichotic listening, crossed tactile finger localization and alternate finger tapping [9–11], and by electrophysiological measurements, in particular the ipsilateral silent period (iSP) [12– 15]. The iSP is elicited by focal transcranial magnetic stimulation (TMS) of one primary motor cortex (MI), and refers to the suppression of voluntary activity in the electromyogram (EMG) of a contracting ipsilateral hand muscle [16– 18]. ISP testing is a simple and little time consuming noninvasive technique that is thought to assess the function of transcallosal fibres mediating the inhibitory effect from the stimulated to the non-stimulated voluntarily active MI of the opposite hemisphere [17,18]. The iSP can be analysed
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according to onset latency, duration, depth and the transcallosal conduction time (TCT). Several studies showed abnormal iSP measures in MS [12–14], but the details of the reported results are rather conflicting. Any of these studies found a different iSP measure to be the most sensitive abnormality (TCT [12]; iSP onset latency [13]; iSP duration [14]). In addition, the reported diagnostic sensitivities of iSP measurements showed large variation, ranging from 80% in early RRMS [14] and 74% in a mixed sample of RRMS and chronic progressive MS [13] to 46% in a mixed sample of RRMS and secondary progressive MS [12]. In contrast, TMS measurements of central motor conduction time (CMCT) are now a diagnostic standard to assess the integrity of the corticospinal tract in patients with definite MS, and many studies reported consistently diagnostic sensitivities between 60% and 80% for both upper and lower limbs [19–22]. The primary aim of this study was to clarify the diagnostic sensitivity of the iSP in identifying abnormalities of callosal conduction in a strictly defined group of patients with clinically early RRMS, using a recently optimised iSP recording protocol [1]. In addition, the relations between iSP and CMCT, and between iSP and morphometric brain MRI measurements, especially of the CC, were examined. 2. Materials and methods 2.1. Subjects and patients Forty-nine patients (22 men and 27 women; aged 23 to 54 years; mean age ± S.D., 35.2 ± 7.6 years) and 20 healthy controls (13 men and 7 women, aged 18 to 44 years; mean age ± S.D. = 29.0 ± 6.6 years) were included in this study, which was approved by the local ethics committee. All patients and controls gave their written informed consent. The healthy subjects were paid for participation. According to the current diagnostic criteria for MS [23], 40 patients were classified as having definite RRMS and 9 patients as having possible MS. In agreement with the MS therapy consensus group [24], all patients with possible MS were recommended to start an immunomodulatory therapy with interferon-beta or glatirameracetate due to positive oligoclonal IgG in the CSF and more than 6 T2 lesions on cranial MRI. Diagnosis had been established 0.9 ± 1.5 years (mean ± S.D.) prior to this study. All patients were investigated (physical examination and electrophysiological measurements) at least 6 weeks after their last relapse in a clinically stable phase. The expanded disability status scale (EDSS) [25] ranged from 0.0 to 4.0 (median = 1.5; mean ± S.D. = 1.3 ± 1.0). 2.2. TMS measures ISP onset latency, iSP duration, iSP depth and TCT were measured in the abductor pollicis brevis (APB) muscle of either hand. Muscle activity was recorded by surface EMG, using Ag–AgCl cup electrodes in a belly–tendon montage. The EMG was amplified, bandpass filtered (0.01–2 kHz)
and digitised (sampling rate, 5.12 kHz, Neuroscreen, Jaeger– Toennies, Höchberg, Germany). Focal TMS was applied to the left or right MI with a figure-of-eight coil (outer diameter of each wing, 90 mm) connected to a Magstim 200 magnetic stimulator (The Magstim Company, Whitland, UK) during maximal voluntary isometric contraction of the ipsilateral APB. These contractions were performed by abduction of the thumb against a rigid manipulandum while the wrist was firmly stabilized by Velcro straps. The coil was held tangential to the scalp. The optimal stimulation site was defined as the coil location that produced consistently largest MEP amplitudes in the contralateral APB. This stimulation site was used for the iSP measurements because it was shown previously that the motor cortical topography of the contralateral MEP and the iSP correspond closely [16,26]. The coil handle pointed backwards, and the angle between the midsagittal plane and the coil handle was approximately 0°, 22.5°, or 45°, according to the individually determined angle that resulted in the longest iSP. The stimulus intensity was set to 80% of maximal stimulator output (MSO). This intensity was selected because it produces stable plateau values for iSP onset latency and iSP duration [17]. For either hand, 15 trials were recorded with a sweep window covering 60 ms prior to and 140 ms after TMS. The intertrial interval was 5–7 s. Short pauses of contraction were allowed to prevent fatigue. The level of voluntary EMG activation was played back via a loudspeaker. This protocol of iSP measurements followed a recently established optimised protocol [1]. The major advantage in comparison to previously used protocols [12–14] is the selection of the APB as the target muscle because the iSP in other small hand muscles, in particular the first dorsal interosseous, may be obscured by a second phase of inhibition that is most likely mediated by an ipsilateral corticospinal pathway rather than by the CC [1,17]. This second phase of inhibition is absent in the APB [1]. In addition, the resting motor threshold (RMT) was determined in the voluntarily relaxed APB to the nearest 1% of MSO. RMT was defined as the minimum stimulus intensity that elicited MEPs N 50 μV in at least five of ten consecutive trials [27]. For CMCT measurements, standard contralateral MEPs were recorded from the APB and tibial anterior (TA) muscles during slight isometric contraction (5%–10% of the maximal strength) using a circular magnetic coil (outside diameter, 140 mm) at a stimulus intensity of 70% MSO [27]. The current direction in the coil, when viewed from above, was counterclockwise for MEP recordings on the right side and clockwise for the left side. In addition, spinal MEPs were elicited by stimulation of cervical and lumbar spinal roots via the circular magnetic coil at a stimulus intensity of 70% MSO. The shortest onset latency of the spinal MEP was defined as the peripheral motor conduction time. CMCTs to the APB (CMCTAPB) and TA (CMCTTA) were calculated by subtracting the peripheral motor conduction time from the shortest onset latency of the cortical MEP [27].
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2.4. Data analysis and statistics
Fig. 1. Illustration of the CC segmentation procedure (modified from [28]) and determination of the pons reference area in a midsagittal T2w MR image of a patient with RRMS. For CC segmentation, the maximal length of the CC (line between the most anterior and posterior points of the CC) was quantified at first. Then perpendiculars were drawn at one-third and one-half of maximal CC length resulting in four callosal segments (CC1–4). CC1 contains the anatomic labels rostrum, genu and rostral body, CC2 corresponds to the anterior midbody, CC3 to the posterior midbody, CC4 comprises the isthmus and splenium. For evaluating the relative atrophy in the four callosal segments, a midsagittal pons reference area was determined. Towards this end, the most posterior point of the pontomedullar cistern was identified (origin of arrow). About 5 mm perpendicular and cranial from this point (arrowhead), a line was drawn orthogonal to the brainstem axis. Then, a second line paralleled this line 5 mm above in the direction of the brainstem axis. Finally, the implied pontine area was marked.
ISP onset and iSP duration were automatically and objectively measured for either hand and individual by means of a previously described graphical method [31]. ISP depth was defined in two different ways: (1) the minimum EMG level during the iSP (dISP-max); and (2) the average EMG level during the iSP (dISP). Both measures were expressed as a percentage of the mean pre-stimulus EMG in the 60 ms prior to the TMS pulse, and these values were subtracted from 100 [16]. The TCT was calculated by subtracting the shortest MEP onset latency from the iSP onset latency in the APB of the same hand. ISP measures and CMCT were considered abnormal if values lay outside the 95% confidence interval of the healthy controls (mean ± 2.5 S.D.). The upper normal limit of CMCTAPB was 9.2 ms, the maximum interside difference 2.0 ms. The upper normal limit of CMCTTA was assessed under consideration of the body length [32]. The upper normal limits of the iSP measures can be derived from Table 1. To evaluate differences of iSP measures between patients and controls, Student's two-tailed t-tests for unpaired samples were applied. Relations between clinical signs of central motor deficits and TMS measures were evaluated with χ2 tests. Spearman's rank order correlation coefficient ρ was determined to examine the relation between iSP duration and MRI measures. A p-value b0.05 was considered significant. All data are presented as means ± S.E.M., unless stated otherwise. 3. Results
2.3. MRI measures 3.1. TMS measures In 28 patients, axial fast fluid-attenuated inversion recovery (FLAIR, TE/TI/TR = 110/2358/9000 ms, flip angle 180°, slice thickness 6 mm, 230-mm field of view, 132 × 256 matrix) and sagittal T2-weighted (T2w, TE/ TR=112/5205 ms, flip angle 180°, slice thickness 3 mm, 230-mm field of view, 270 × 512 matrix) MR brain images were acquired with a 1.5-T scanner. Brain lesion number and volume were determined in both axial FLAIR (supratentorial lesions) and sagittal T2w (brainstem and cerebellar lesions) images. Midsagittal T2w MR images were aligned to the anterior commissure (AC)–posterior commissure (PC) plane. The CC was then segmented into 4 subregions (CC1–4, Fig. 1), similar to a previously described method [28]. The CC volume (ml) was computed by summation of the CC area (mm2) in 4 adjacent T2w sagittal slices in which the CC could be clearly differentiated from the cingulate gyrus, and by multiplication of the resultant area with the section interval (3.3 mm)/1000. Relative CC atrophy was defined as the percentage of the midsagittal CC area compared to a midsagittal pons reference area (Fig. 1). This reference area was chosen because the pons, in contrast to the CC, is relatively little affected in RRMS by local tissue damage and regional atrophy [29,30].
There were no differences in RMT between RRMS patients and healthy controls (right APB, 39.3 ± 1.1% MSO vs. 39.1 ± 1.1% MSO, respectively; left APB, 39.7 ± 1.2% MSO vs. 40.3 ± 1.4% MSO, respectively). Since stimulus Table 1 Comparison of iSP measures between healthy control subjects (n = 20) and patients with early RRMS (n = 49) Measure
Controls Patients Points with (mean ± S.D.) (mean ± S.D.) abnormal measure (%)
iSP onset latency (ms) iSP duration (ms) TCT (ms) dISP-max (%) dISP (%) Side difference: iSP onset latency (ms) Side difference: iSP duration (ms) Side difference: TCT (ms)
35.6 ± 4.3
34.9 ± 4.7
4.1
26.4 ± 5.2 15.0 ± 3.2 77.9 ± 4.9 56.0 ± 6.9 3.4 ± 2.5
32.3 ± 9.0⁎ 13.6 ± 4.2 76.1 ± 10.0 56.4 ± 9.5 3.6 ± 3.9
22.4 6.1 6.1 2.0 2.0
4.1 ± 3.0
5.8 ± 6.4
12.2
2.8 ± 2.4
3.4 ± 3.4
6.1
⁎ p b 0.01; normative limits were defined by mean ± 2.5 S.D.
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Fig. 2. Example of iSP recordings from an RRMS patient with unilateral prolongation of iSP duration in the left APB (right panel). Data are averages from 15 single-trial rectified sweeps. Horizontal lines indicate the calculated upper and lower variation limits of the pre-stimulus EMG; the resulting iSP onset and offset latencies are indicated by the vertical dashed lines.
intensity for the iSP measurements was set to 80% MSO (see methods), this is an important negative result which rules out that differences in relative stimulus intensity have accounted for the obtained differences in iSP measures between patients and controls (see below). There were also no significant differences in the level of the mean pre-stimulus EMG or the variance of the prestimulus EMG, expressed as the mean consecutive difference of successive data points in the mean pre-stimulus EMG, between RRMS patients and healthy controls (mean level: 0.31 ± 0.17 mV vs. 0.38 ± 0.27 mV, mean consecutive difference: 0.017 ± 0.008 mV vs. 0.021 ± 0.011 mV) that could have affected the comparison of iSP measures between the two groups. ISP duration was significantly longer in the RRMS patients compared to healthy controls (32.3 ± 1.2 ms vs. 26.4 ± 1.2 ms, p b 0.005), while no significant differences were detected for iSP onset latency (34.9 ± 0.6 ms vs. 35.6 ± 1.0 ms), TCT (13.6 ± 0.5 ms vs. 15.0 ± 0.7 ms), dISP-max (76.1 ± 1.8% vs. 77.9 ± 0.8%) or dISP (56.4 ± 1.6% vs. 56.0 ± 1.1%). Consequently, iSP duration was the most sensitive iSP measure (Table 1 and
Fig. 3. Numbers of RRMS patients (n = 49) with abnormalities of iSP measures (upper left circle), CMCTs to the APB (upper right circle) and CMCTs to the TA (lower circle). No abnormalities were detected in 12 patients. Only 3 patients had abnormalities exclusively in the iSP measures. Note that iSP measurements add little to the diagnostic work-up in early RRMS.
Fig. 2). Additional consideration of pathological interhemispheric differences of the iSP measures resulted in only a small increase of abnormal findings (Table 1). The combined percentage of pathological findings of all iSP measures (at least one abnormal finding in a given patient) was 28.6%. This diagnostic sensitivity was similar as for CMCTAPB (24.5%) but much lower than the one for CMCTTA (69.4%). In only 3 out of 49 patients (6.1%), iSP measures were the only abnormal finding (Fig. 3). Abnormalities in iSP occurred more frequently when CMCTAPB to the same hand was prolonged compared to when it was normal (40.0% vs. 8.4%; p b 0.0001, 98 hands). Accordingly, the iSP duration was longer when CMCTAPB to the same hand was prolonged compared to when it was normal (39.6 ± 3.8 ms vs. 31.2 ± 0.8 ms, p b 0.002, 98 hands, Fig. 4). The correlation between iSP duration and CMCTAPB to the same hand was significant but weak (Pearson's r = 0.24, p b 0.02).
Fig. 4. ISP duration (mean ± 1 S.D.) in patients with RRMS grouped according to whether CMCTAPB to the same target muscle was normal (left, nCMCT) or prolonged (right, pCMCT). Note that iSP duration was significantly longer in the group with prolonged CMCTAPB.
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3.2. Relation of TMS measures to clinical findings 51.0% of the RRMS patients had clinical central motor signs in the past or at present of at least one arm (20.4%) and/or one leg (49.0%). The percentage of abnormal CMCTAPB findings differed significantly between patients with vs. without previous or current clinical central motor signs of at least one arm (45.5% vs. 11.5%, p b 0.005, n = 98), while the percentage of abnormal iSP measures was not significantly different between these two groups (27.3% vs. 14.9%). Further, there was no significant difference of the percentage of abnormal CMCTTA between patients with vs. without clinical central motor signs of the lower limbs (73.1% vs. 56.9%). There were no significant differences in the percentage of abnormal findings for CMCTAPB, CMCTTA or iSP for patients with definite RRMS compared to those with possible RRMS. 3.3. Relation of iSP measures to MRI findings The 28 RRMS patients in whom an MRI was obtained at the time of the TMS investigations had a mean number of brain lesions of 15 ± 2, the mean total volume of brain lesions was 11.8 ± 2.5 ml. A large portion of patients (78.6%) showed at least one visible T2 lesion in the CC, and the mean number of lesions in the CC was 3 ± 1. CC lesions were mostly wedgeshaped with the extended basis pointing inferiorly. In terms of lesion volume, the CC was on average only mildly affected with a mean value of 5.6 ± 1.3% (CC1, 5.5 ± 1.3%; CC2, 7.9 ± 2.0%; CC3, 6.0 ± 1.7%; CC4, 5.0 ± 1.5%). The midsagittal area of the whole CC was 555.2 ± 15.9% of the midsagittal pons reference area (CC1, 225.4 ± 6.5%; CC2, 62.7 ± 2.1%; CC3, 55.8 ± 1.8%; CC4, 211.3 ± 7.5%). The mean size of the midsagittal pons reference area was 109.7 ± 1.9 mm2 and none of the patients showed T2 lesions in that area. Correlations between iSP duration, the most sensitive iSP measure, and brain lesion number (ρ = − 0.082), brain lesion volume (ρ = 0.038), lesion number of the whole CC and CC segments 1–4 (ρ = 0.114–0.292), percentage lesion volume of the whole CC and CC segments 1–4 (ρ = − 0.066–0.248), or relative atrophy of the whole CC and the four CC segments (ρ = − 0.075 to − 0.185) were all not significant. Moreover, none of the investigated MRI measures showed a significant difference between MS patients with a pathologically prolonged vs. normal iSP duration (Mann–Whitney U tests). The most distinct, albeit not significant, difference was detected for the relative atrophy of CC3 between the two groups, with a more pronounced relative CC3 atrophy of the patients with a prolonged vs. normal iSP (49.5 ± 3.9% vs. 57.5 ± 1.9%, p = 0.08). 4. Discussion By applying an optimised iSP recording protocol [1], we were unable to replicate the superior sensitivity of iSP measures in comparison to standard CMCT measurements found in previous studies of MS patients [13,14]. In those
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studies, iSP recordings were made in the first dorsal interosseous (FDI) muscle. We demonstrated in a study of healthy subjects that a second phase of inhibition that merges into the preceding iSP occurs frequently in the FDI but almost never in the APB [1]. Very likely, this second phase of inhibition is not mediated via the CC but rather represents inhibition along an ipsilateral corticospinal projection because it persisted at least in some patients with a complete agenesis of the CC while the iSP was always absent in these patients [17]. Therefore, it is difficult to estimate to which extent the high diagnostic sensitivity of iSP measures in the previous studies [13,14] was caused by dysfunction of the CC, or dysfunction of the putative ipsilateral corticospinal pathway, or both. Although iSP measures to the APB are not contaminated by this second phase of inhibition, and thus may assess callosal conduction abnormality more specifically, other problems exist (contamination of iSP measures by corticospinal tract demyelination, lack of correlation to MRI measures of CC lesion or CC atrophy) that will be discussed in detail in the following paragraphs. 4.1. Possible mechanisms of abnormal iSP duration It is currently thought that the iSP reflects an inhibition of voluntary corticospinal activity in the non-stimulated MI, elicited by focal TMS of the other MI and mediated through the CC [17,18]. Therefore, a prolongation of iSP duration could be explained by involvement of either the CC or the corticospinal tract that originates from the non-stimulated MI. Partial demyelination of callosal fibres will result in a normal iSP onset through normally conducting fibres but dispersed iSP transmission through demyelinated fibres. This, in turn, will lead to a delayed iSP offset. Partial demyelination of corticospinal tract fibres that originate in the non-stimulated M1 and project to the target muscle ipsilateral to the stimulated M1 will result in a normal iSP onset from interruption of voluntary activity in normally conducting fibres, but dispersed transmission of resumption of voluntary activity along demyelinated fibres. This, in turn, will also lead to a delayed iSP offset. The present data support a role for this second mechanism because iSP duration was significantly more often prolonged if CMCTAPB to the same target muscle was also abnormal (Fig. 4), and iSP duration correlated significantly with CMCTAPB. In accordance with these observations, it was previously noted that an abnormal CMCT to the FDI was always associated with abnormal iSP measures, in particular iSP duration [15]. Therefore, it is very likely that iSP duration does not assess specifically demyelination of callosal motor fibres but, in addition, demyelination of the fibres of the contralateral corticospinal tract. This conclusion gains additional support from the present finding that the TCT, which is calculated by subtraction of the shortest MEP latency from the iSP onset latency in the APB of the same hand, and therefore should address more specifically demyelination of callosal motor fibres, showed a much lower diagnostic sensitivity (6.1%) than iSP duration (22.6%).
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4.2. Relation of iSP measures to MRI findings ISP sensitivity was low (28.6%) despite macroscopically visible CC lesions on MRI in a high proportion of patients (78.6%), and there were no significant correlations between iSP duration and MRI measures of CC lesion load or CC atrophy. In addition to the problem that our data suggest that the iSP duration does not specifically address conduction abnormalities of the CC but is contaminated by demyelination of the contralateral corticospinal tract, there exist several other potential explanations for the discrepancy between iSP and MRI measures. First, iSP duration addresses demyelination, while MRI measures reflect other pathology such as inflammation (T2w lesion) or axonal degeneration (MRI measures of atrophy). This view is supported by previous studies which showed that composite evoked potential scores relate closely to clinical disability in MS [33,34] while this is the case to only a much lesser extent for MRI measures, in particular T2w lesion load [33,35]. Another explanation for the dissociation between iSP and MRI measures is that the CC was frequently but only mildly affected on T2w MRI. However, the present findings demonstrated a trend towards a higher relative atrophy specifically of the CC3 (i.e. the posterior body of the CC) in the patients with a pathologically prolonged iSP duration compared to those with a normal iSP duration. This is consistent with recent data in humans that identified the posterior body and isthmus of the CC as the site where the transcallosal fibres connecting the MI of the two hemispheres are located [18,36]. Finally, in non-human primates, there exist only few [37,38] but presumably functionally significant transcallosal fibres between homologous hand representations of MI in the two hemispheres although the total quantity of transcallosal fibres in humans is large [39]. For this reason, the stochastic probability for damage of the relatively few and short transcallosal motor fibres is low, especially in patients with early RRMS, in whom the CC lesion volume is usually small. In contrast, the corticospinal projection to the lower limbs, according to its much longer length, should have a higher risk for demyelination. In summary, it is plausible that, for these various reasons, iSP measures are not a sensitive electrophysiological marker to detect abnormal conduction across the CC in clinically early RRMS. This is supported by the present study and previous data [12]. 4.3. Significance and conclusions This study strongly suggests that the iSP does not assess specifically conduction along the corpus callosum. Conduction abnormality along the contralateral corticospinal tract may contribute to the alteration of iSP measures. This places a caveat as to the interpretation of abnormal iSP data in other studies that increasingly often use the iSP to identify callosal conduction abnormality in neurological disorders with potentially confounding involvement of the corticospinal tract [40,41]. For the reasons of unclear topographic specificity
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