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Consistency of evoked responses to dual-stimulator, single-pulse transcranial magnetic stimulation in the lower limb of people with multiple sclerosis
Journal of Clinical Neuroscience, Volume 22, Issue 9, September 2015, Pages 1434 - 1437
The purpose of this study was to explore the within session and test–retest consistency of motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) from the resting tibialis anterior (TA) muscle of 10 patients (two men, eight women) with clinically definite multiple sclerosis (MS). Dual stimulators were configured to produce a single pulse (DS/SP) through a hand-held coil. MEP were recorded in five blocks of five trials with a repeat test occurring 7–14 days later. Analysis of a trial sequence revealed the area of the first MEP trial of each block to be significantly different to subsequent trials (trials 2–5; p < 0.05). We therefore discarded T1 from further analysis. Thereafter, repeated measures of analysis of variance of MEP characteristics and blocks of MEP (average of four trials) revealed no significant differences (p > 0.05). The results of the repeat session revealed no significant differences in motor thresholds, MEP latency, MEP amplitude or MEP area between sessions (p > 0.05). Test–retest intra-class coefficients of correlation and their 95% confidence intervals indicated high reliability (>0.80). Our results show that consistent, repeatable TMS measures can be obtained from the resting TA of MS patients using the DS/SP method.
Keywords: Dual stimulators, MEP, Multiple sclerosis, Reliability, Single pulse, Transcranial magnetic stimulation.
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterised by demyelination, neurodegeneration , , and  and progressive axonal loss causing variable levels of autonomic, physical and cognitive deterioration  and . Physical impairments are particularly distinct in the lower body where incomplete motor unit activation and altered muscle characteristics are similar to those reported in hemiplegia and spinal cord injury  and . Transcranial magnetic stimulation (TMS) studies of the lower body using conventional single stimulator configurations (SSTIM) are often confounded by disease related frequency dependent conduction block and complete conduction block  that cause prolonged central motor conduction times (CMCT)  and , higher motor thresholds (MT)  and  and reduced motor evoked potential (MEP) size  and . Moreover, the higher SSTIM intensities required to evoke MEP in the lower limb of MS patients evoke repetitive corticospinal discharges producing prolonged, complex, polyphasic wave forms  . MEP areas change considerably and unpredictably from one stimulus to the next  . Temporal dispersion resulting from the de-synchronisation of descending action potentials and phase cancellation further affect MEP in an unpredictable manner  and . As a consequence, some investigators have found the interpretation of MEP from MS patients to be impeded to such an extent that they have described the only robust MEP amplitude criterion as lack of response  .
When considering the methodological difficulties of SSTIM to elicit MEP from the lower limbs of people with MS  and , a dual stimulator configuration set to fire a single pulse (DS/SP) presents an attractive alternative method. When two stimulators are configured to fire simultaneously through a single coil, although the electrical field of the pulse is increased to ∼113% of SSTIM  , the duration of the pulse is prolonged by ∼140%  . In healthy subjects, increased pulse durations have been observed to significantly reduce the variability of MEP and decrease motor thresholds by ∼20% in both active and resting muscle  . However, the method remains to be tested in patients with a neurological condition. Therefore, the purpose of this study was to explore the internal stability, consistency and reproducibility of responses to DS/SP elicited from resting muscle in the lower limb of MS patients.
Participants with clinically definite MS  confirmed by a consultant neurologist attended sessions at the Nuffield Orthopaedic Centre, Oxford. Ethical approval was obtained from the Oxfordshire Research and Ethical Committee (07/H0604/84). The investigation was conducted within published safety guidelines for the application of TMS in clinical practice and research  . Participants completed TMS safety screening questionnaires  and signed an informed consent document in accordance with the Declaration of Helsinki. Exclusion criteria were in accordance with published safety guidelines  . Prior to the experiment, patients refrained from smoking and ingesting caffeine or alcohol for at least 3 hours.
2.1. TMS data acquisition
TMS was administered on two separate occasions (7–14 day intervals). Participants lay semi-supine on a two section medical examination plinth with their bodies angled at 30° of an upright position. The target muscle was the tibialis anterior (TA) on the dominant side of the body (tested by dynamometer). Skin lying under the electrodes was cleaned with an alcohol swab. Paired silver chloride surface electrodes (T3404, Thought Technology, Ltd., Montreal West, Quebec, Canada) were positioned with an inter-electrode distance of 20 mm over the middle of the muscle in line with its longitudinal contour. Electrode locations were carefully noted for precise replacement during the next visit. Twisted paired cables connected the electrodes to a four channel pre-amplifier (Neurolog 844; Digitimer, Ltd., Hertfordshire, UK).
Two magnetic stimulators connected to a Bistim2 module (Magstim Company, Carmarthenshire, UK) were configured to produce a single pulse from a double, cone shaped coil (110 mm). The hand-held coil was placed parallel to and ∼0.5–1.5 cm lateral to the midline with its midpoint aligned antero-posteriorly against the vertex  and . The coil was moved systematically until the hotspot was identified and marks on the scalp were made with an indelible ink pen.
The MT of each patient was determined by reducing power in 5% increments until stimulus artefacts disappeared. Stimulator output was then increased in 1% increments until the threshold was reached (five or more MEP with amplitudes of >50 μV in at least five of 10 successive stimuli from the relaxed target muscles)  . The experiment was conducted at 120–130% MT.
TMS was delivered in five blocks of five trials (T1–T5) with intervals of 7–10 seconds between each trial and 5 minutes between each block. Electromyography (EMG) signals were recorded through a Neurolog 820 (Digitimer, Ltd.) relayed to a CED Micro1401 (Cambridge Electronic Design, Cambridge, UK), amplified (×1000) and filtered with a band pass filter of 1000 Hz to 10 Hz. A 55 Hz notch filter was applied. The data was digitised at 2000 Hz and stored for further analysis on a computer.
2.2. Data analyses
Recordings were analysed using Signal (version 3.11; Cambridge Electronic Design). MEP were full wave rectified  and calculated as the product of the mean amplitude multiplied by the duration (ms), taken as the area under the line delimited by vertical cursors  . MEP were measured from the deflection point of the leading edge of the stimulus artefact above the background EMG to the inflection point on the trailing edge of the longest waveform above background EMG.
MEP contaminated by artefact or showing evidence of voluntary activation during the 20 ms pre-stimulus window and post-stimulus latency period were excluded (<2% of trials per session). The data was imported into SPSS statistics software (version 17.0; IBM Corporation, Armonk, NY, USA) for statistical analyses. Demographic data was explored using descriptive statistics. Firstly, repeated measures analysis of variance (ANOVA) compared trials in sequence (T1–T25). Trials were then averaged into five blocks and analysed. When ANOVA revealed a significant main effect, tests of within patient contrasts were used to determine the specific trial or block. To compare measures between sessions, paired two tailed t-tests were supported by intra-class correlation coefficients (ICC) and their 95% confidence intervals (CI).
Responses to TMS were obtained from the TA of 10 patients (two men, eight women; mean age 51.07 ± standard deviation [SD] 9.8 years; mean height 169 ± SD 9 cm; MS categorisation: five relapsing-remitting, five secondary progressive; disease duration mean 12.8 ± SD 9.6 years). Mean tympanic temperatures were 36.6 ± SD 0.4°C and 36.5 ± SD 0.3°C for sessions 1 and 2, respectively.
The DS/SP configuration produced a pulse with a magnetic field rise of 176 ms at 100% output. None of the participants reported adverse effects in response to TMS. Analysis of the trial sequence revealed the first MEP of each block (T1) to be significantly larger than T2–T5 ( Table 1 ). Following this, T1 was discarded from further analyses. Paired two tailed t-tests and ICC with respective 95% CI based on a two way, mixed effect model with absolute values revealed no difference between session measures of mean motor threshold (p > 0.05), mean MEP latency (p > 0.05), mean peak MEP amplitudes (p > 0.05) and MEP areas between sessions (p > 0.05; Table 2 ). Repeated measure ANOVA of blocks constructed from the averages of four trials (T2–T5) revealed no significant differences within patients between sessions (p > 0.05) and test–retest ICC and 95% CI indicated high reliability (>0.80; Table 2 ).
|MEP area (mV × ms)||F||p value||Partial eta2|
|T2 versus T1||4.674||0.036||0.087|
|T3 versus T2||0.001||0.974||0.000|
|T4 versus T3||0.798||0.376||0.016|
|T5 versus T4||0.002||0.964||0.000|
Note: Repeated measures one-way analysis of variance determined the effect of trial order. Each group consisted of 49 trials in their respective order from each block.
eta2 = measure of effect size, F = ratio of variances, MEP = motor evoked potentials, ms = mean duration, mV = mean amplitude, T1 = trial 1 (et cetera).
|TMS measure a||Session 1||Session 2||ICC||95% CI|
|Motor threshold (% MSO)||48.4 ± 4.8||48.7 ± 4.7||0.992||0.947||0.948|
|CMCT (ms)||35.1 ± 6.9||35.4 ± 7.2||0.993||0.972||0.988|
|MEP area (mV × ms)||5.8 ± 6.6||7.0 ± 7.0||0.957||0.765||0.991|
|MEP peak amplitude (mV)||398 ± 347||396 ± 449||0.916||0.683||0.980|
|MEP block b|
|1||Area||5.12 ± 6.41||6.69 ± 8.57||0.897||0.601||0.978|
|Peak amp||306 ± 320||430 ± 521||0.832||0.441||0.959|
|2||Area||3.14 ± 3.65||4.25 ± 4.25||0.849||0.406||0.972|
|Peak amp||248 ± 261||273 ±239||0.891||0.566||0.977|
|3||Area||5.66 ± 6.92||7.97 ± 8.89||0.894||0.514||0.977|
|Peak amp||330 ± 419||413 ± 482||0.949||0.759||0.989|
|4||Area||6.19 ± 6.82||7.26 ± 8.10||0.948||0.798||0.988|
|Peak amp||262 ± 285||339 ± 481||0.812||0.354||0.949|
|5||Area||4.72 ± 6.12||6.31 ± 5.79||0.903||0.567||0.978|
|Peak amp||188 ± 225||296 ± 325||0.812||0.275||0.960|
a TMS measures are shown as the mean ± standard deviation.
b Blocks consisted of four MEP (T2–T5).
% MSO = percent of maximum stimulator output, amp = amplitude, CI = confidence interval, CMCT = central motor conduction times, ICC = intra-class correlation coefficient, MEP = motor evoked potentials, MEP area = mean duration × mean amplitude, mV = peak amplitude, TMS = transcranial magnetic stimulation.
To our knowledge, this was the first study to explore the effects of DS/SP TMS in MS patients. Demographic analyses of trial order found the first MEP of each block (T1) to be significantly larger than subsequent trials (T2–T5). This artefact has been previously reported in TMS studies of healthy adults  and is thought to reflect an initial facilitation,  perhaps in anticipation of further TMS stimuli  . We excluded T1 from further analyses. Thereafter, individual trials (T2–T5) and blocks averaging four trials remained stable over the 20 minute period. There was a great deal of heterogeneity between individuals’ responses to TMS, however, when re-tested 7–14 days later, the recordings of patients’ motor thresholds, MEP latencies, MEP area and amplitudes remained consistent. ICC of blocks of four MEP demonstrated high levels of reliability (>0.80)  . Indeed, after excluding T1, the results suggest the DS/SP method can produce consistent reliable baseline measures from the averages of just two trials. The higher inter-individual variability and higher ICC values with respective 95% CI obtained within a session rather than on separate days, in addition to the lack of bias in data recorded both within a session and on separate days, together suggest that variability in MEP was due to inherent, time varying individual neurophysiological processes rather than measurement bias. Nevertheless, we accept our findings are limited by the small number of MS patients taking part, and further studies are recommended.
The results of this study show that consistent, repeatable TMS measures can be obtained from resting muscle in the lower limb of MS patients using this methodology. Collecting a low number of repeats for the baseline may limit sensitivity to change, and post-intervention responses can display low levels of change with increased variability. Therefore, for a baseline measure, we recommend obtaining at least four MEP after eliminating the first trial.
Conflicts of Interest/Disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
We are grateful to Sam Jacobs from The Magstim Company, Ltd. for his technical assistance with the measurement of the magnetic pulse. This work was supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland [grant number 840/06].
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