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Triple Stimulation Technique in Amyotrophic Lateral Sclerosis

Wang, Yue*; Wang, Han; Cui, Li-Ying†,‡

Journal of Clinical Neurophysiology: March 2019 - Volume 36 - Issue 2 - p 87–92
doi: 10.1097/WNP.0000000000000520
Original Research

Purpose: To identify upper motor neuron (UMN) dysfunction using the triple stimulation technique (TST) in amyotrophic lateral sclerosis (ALS).

Methods: Fifty ALS and 42 non-ALS patients were examined clinically, using conventional transcranial magnetic stimulation and TST.

Results: For ALS patients presenting with UMN in tested limb, the TST amplitude ratio was abnormal in 25 of 28 patients (89.3%). For ALS patients without UMN signs, 6 of 22 patients (27.3%) had an abnormal TST ratio. When clinical signs were not present, both abnormal resting motor threshold and TST indicated a UMN involvement. In non-ALS patients with central motor conduction disorders, the percentage of patients with an abnormal TST was higher for those presenting with clinical UMN signs (9/12, 75.0%) than for those without these signs (1/8, 12.5%).

Conclusions: Triple stimulation technique appears to be an accurate, early measure for detecting clinical and subclinical UMN abnormalities in ALS. Triple stimulation technique could also be useful to investigate central motor conduction abnormalities in other disorders.

*Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China;

Department of Neurology, Peking Union Medical College Hospital, Beijing, China; and

Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China.

Address correspondence and reprint requests to Cui Li-Ying, MD, Shuaifuyuan 1, Wangfujing St, Dongcheng District, Beijing 100730, China; e-mail:

The authors have no conflicts of interest to disclose.

Supported by China Ministry of Science and Technology Study on accurate diagnosis and treatment techniques and clinical norms of important rare diseases (2016YFC0905103); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-12M-1-004); Tianjin University of Science and Technology (20140110).

Transcranial magnetic stimulation (TMS) is a promising technique for assessing the functional integrity of the corticospinal tract in amyotrophic lateral sclerosis (ALS) by measuring motor evoked potentials (MEPs) and central motor conduction times (CMCTs). However, this technique has a low sensitivity for the detection of upper motor neuron (UMN) dysfunction.1–4 Although MEPs should theoretically reflect the number of conducting central motor neurons, MEP amplitude variability, which is related to the desynchronization of descending volleys, obscures an assessment of the number of activated motor neurons. Additionally, CMCT has been reported to be either normal or modestly prolonged in most ALS patients, as it is not directly correlated to the number of UMNs lost.5 Thus, MEP and CMCT, as well as other electrophysiological measurements, are apparently unable to detect accurately corticospinal tract impairments in ALS. Consequently, the presence of clinical signs of UMN dysfunction has remained the “gold standard” for ALS, although UMN signs may not be clearly apparent when a superimposed lower motor neuron (LMN) dysfunction is present. Some patients without clinical UMN signs were initially diagnosed with progressive muscular atrophy but developed clinical UMN signs later, thus changing the diagnosis to ALS.

Rösler et al.5,6 have recently explored the triple stimulation technique (TST) and found that it detects UMN dysfunction in ALS with a high sensitivity. In the current prospective study, we examined whether TST proves to be an accurate method for detecting clinical and subclinical UMN abnormalities and allows a quantification of UMN impairments.

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The selection of ALS patients was based on the El Escorial criteria.7 In this study, 50 patients were enrolled, including 5 with clinically definite, 19 clinically probable, 24 clinically probable and laboratory supported, and 2 clinically possible forms of ALS. Additionally, 42 subjects not presenting with ALS were included: 12 patients with other central motor disorders presenting clinical signs of UMN involvement (cerebrovascular disorders, 5; multiple sclerosis, 3; C1-C4 segment cervical spondylotic myelopathy, 4), 8 patients with peripheral nerve disorders having no clinical UMN signs (polyneuropathy, 4; Hirayama disease, 2; spinal muscular atrophy, 1; genetically confirmed Kennedy disease, 1), and 22 healthy age- and sex-matched control subjects. The experimental protocol was approved by the local ethics committee, and all subjects gave written informed consent.

At the beginning of the study, the same physician assessed all patients with a physical examination and the Revised ALS Functional Rating Scale.8 Muscle power in the abductor digiti minimi was graded according to the British Medical Research Council scale (MRC grade 1–5; severe paresis, grade 1; full muscle strength, grade 5).9 The presence of a brisk tendon reflex, an increased muscle tone, or the Hoffmann sign was used as an indicator of a UMN deficit, which was tested in the right upper limb.10 Fasciculation, muscle atrophy, and muscle weakness without UMN signs were considered clinical LMN signs. The patients were assigned to one of five clinical groups: group A (28 ALS patients with UMN signs in the tested extremity), group B (22 ALS patients without UMN signs in the tested limb, but with signs in other extremities), group C (12 non-ALS patients with a pure UMN syndrome), group D (8 non-ALS patients with a pure LMN syndrome), or group E (22 control subjects showing no UMN or LMN signs).

Clinical evaluation of upper limb spasticity was performed using the Modified Ashworth Scale during passive elbow flexion and extension with the patient lying supine.11,12 All 50 clinical suspected ALS patients included were followed up for up to 2 years. All have an ALS diagnosis confirmed either by disease progression or by decease. None of the patients were treated with anticonvulsants.

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Conventional TMS

In this study, all TMS parameters were evaluated in the patients' right abductor digiti minimi. The abductor digiti minimi was chosen because of the limited volume conduction from other muscles that are also depolarized by stimuli over the scalp and at Erb point.13 Nerve conduction studies were performed using standard techniques. Patients with severe atrophy were excluded, i.e., with compound muscle action potentials for the wrist (CMAPwrist) below 2 mV. The CMAPerb was obtained with supramaximal electrical stimulation at Erb point. Supramaximal stimuli were always used for peripheral nerve stimulation using a Viking Select EMG machine (Keypoint, Dantec, Denmark). Method of conventional TMS measurement was determined according to international guidelines.14,15 Transcranial magnetic stimulation was delivered to the left motor cortex via a Medtronic MagPro stimulator and a figure-8-shaped coil, MC-B70 (Medtronic Functional Diagnostics, Skovlunde, Denmark). The signal bandpass was set to 2 to 10 kHz. Resting motor threshold (RMT) and CMCT were recorded and subsequently analyzed.

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Triple Stimulation Technique

The TST has been described in detail previously.16 In short, TMS was combined with two supramaximal electrical stimuli delivered to the ulnar nerve at the wrist and at Erb point at appropriate interstimulus intervals. The delays between the three stimuli were calculated as follows: Delay I (brain–wrist) = minimum MEP latency − CMAPwrist latency; Delay II (Erb point–wrist) = CMAPerb latency − CMAPwrist latency. The TSTtest curve was then compared with the TSTcontrol curve by replacing the TMS with the maximal electrical stimulus to the ulnar nerve at Erb point. The TST amplitude was expressed as the ratio of TSTtest to TSTcontrol, termed TST amplitude ratio.

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Statistical Analysis

Statistical analyses were performed using SPSS13.0. Sensitivity was defined as the percentage rate of abnormal findings. To test the significance of differences for TST amplitude ratios between two groups, normality tests and nonparametric tests were applied (Mann–Whitney test for two, Kruskal–Wallis test for multiple group comparisons). The chi-square test was used to test differences in the rates of abnormal findings between groups. Correlations between various parameters were analyzed by performing Spearman nonparametric correlation test. The level of significance was set at P < 0.05.

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Ninety-two patients were examined using the procedures outlined above, and no adverse effects were observed subsequently. Patients' information is shown in Table 1. The ALS patients had a mean duration of symptoms of 12 months (range, 5–60 months). Eight ALS patients presented with bulbar onset and 42 with limb onset. Control values were obtained from 22 healthy subjects, and values in the 2.5 SD range were considered as normal in healthy probands. Thus, the following values were established as normal: CMCT < 8.8 ms; TST amplitude ratio > 90%; RMT 35% to 65%.



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Clinical and Electrophysiological Findings in ALS Patients

An example of a TST recording is shown in Fig. 1. Technically, recordings were not more difficult to obtain from ALS patients than from healthy subjects or from patients with other central motor conduction disorders. The numbers of patients in each group with abnormal conventional TMS or TST parameters are shown in Table 2.

FIG. 1

FIG. 1



Group A comprised 28 ALS patients showing clinical signs of UMN involvement, whereas 22 ALS patients in group B exhibited no clinical UMN signs in the tested limb. The mean value of TST amplitude ratios was significantly lower in group A compared with group B (Z = −4.827, P < 0.001, Fig. 2). The TST amplitude ratio in group A was abnormal in 25 of 28 patients (89.3%), whereas this parameter was abnormal in 6 of 22 patients (27.3%) in group B. Thus, clinical UMN signs of ALS patients were nearly always accompanied by a corticospinal conduction deficit as measured by the TST amplitude ratio, which are therefore highly significantly associated (χ2 = 14.845, P < 0.001).

FIG. 2

FIG. 2

The sensitivities to detect these abnormalities using conventional TMS in group A were 18 of 28 (64.3%) for MEP and CMCT and 22 of 28 (78.6%) for RMT, which were markedly lower than the 89.3% detected by TST. Thus, TST was more sensitive than conventional TMS. The comparison between TST and conventional TMS parameters is shown in Table 3.



However, the correlation between clinical and electrophysiological signs of UMN loss was not absolutely consistent. A normal TST amplitude ratio was found in 3 of 28 (10.7%) group A patients with clinical UMN signs. Conversely, an abnormal TST amplitude ratio was found in 6 of 22 (27.3%, group B) patients without UMN signs. Of those, two also showed an increased RMT. Further clinical examination revealed severe proximal weakness in their upper limbs. The consistent abnormality of RMTs and TST amplitude ratios suggested that their UMN was involved despite the lack of clinical UMN signs. These patients ultimately developed definite ALS, which suggests that these two techniques used together had shown a subclinical UMN involvement.

For the 50 ALS patients, a strongly significant negative correlation was found between TST values and RMT (ρ = −0.774, P < 0.001) and between TST and Modified Ashworth Scale (ρ = −0.772, P < 0.001). However, no correlation was detected between TST values and the following parameters: muscle strength of the right abductor digiti minimi (ρ = 0.142, P = 0.324), CMAPwrist (ρ = −0.093, P = 0.522), Revised ALS Functional Rating Scale (ρ = −0.028, P = 0.848), and disease duration (ρ = −0.112, P = 0.437).

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Clinical and Electrophysiological Findings in Non-ALS Patients With Central Motor Conduction Disturbances

The 20 patients without ALS were split into 2 groups according to the presence or absence of clinical UMN signs. Group C comprised 12 non-ALS patients with clinical signs of UMN involvement. Eight non-ALS patients with no clinical UMN signs were in group D. The mean value of TST amplitude ratio was also significantly lower in group C compared with group D (Z = −2.086, P = 0.037, Fig. 2), and no significant difference was found between group C and group A (Z = −0.946, P = 0.344). The abnormal TST amplitude ratios found in group C patients (9/12, 75.0%) were significantly more often than those in group D (1/8, 12.5%; χ2 = 7.500, P = 0.006). Thus, the average decrease in the TST amplitude ratio was more marked in non-ALS patients with a pyramidal syndrome than those without a pyramidal syndrome. Clinical UMN signs in non-ALS patients were also accompanied by abnormal TST amplitude ratios.

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The main finding obtained in this study was the existence of a significant association between the TST amplitude ratio and UMN dysfunction in both ALS patients and non-ALS patients. Indeed, TST may reveal subclinical UMN impairments in ALS patients.

It is supported by the data presented in this study that an abnormal TST amplitude ratio is a sign for a UMN involvement in ALS. First, 89.3% of ALS patients with clinical UMN signs showed a reduced TST amplitude ratio, which was a much higher proportion than the 27.3% of ALS patients not exhibiting those signs. Second, there was a significant difference in TST amplitude ratios between groups with and without clinical UMN signs. Thus, a significant association was found between clinical and TST assessments of UMN involvement in ALS. In the ALS patients in group A, the frequency of 89.3% for UMN involvement detected by abnormal TST ratios was a little higher than the previously reported 66.7% in ALS patients with clinical UMN signs.17 The frequency of abnormal TST ratios in all ALS patients, i.e., groups A and B, was 62%, which is similar to 55.6% in Attarian et al.,17 but much lower than Komissarow's detection rate of 84% in all ALS patients.18 These discrepancies may be accounted for by a higher incidence of absent MEPs that was observed in our study (without excluding variations caused by different coils such as figure of eight vs. circular coil). To summarize, the frequency of abnormal TST amplitude ratios was significantly increased in ALS patients presenting with clear UMN signs compared with those without.

However, discrepancies between clinical UMN signs and TST amplitude ratios were found in ALS patients with UMN signs. A normal TST amplitude ratio was found in 10.7% of ALS patients showing clinical UMN signs. In theory, the TST ratio should not be affected by the loss of LMNs. However, in a study investigating the effects of heavy LMN loss,19 the TST amplitude ratio was either 0 or 100% for a given patient. Therefore, the TST response is a less reliable measure of UMN loss when accompanied by severe loss of LMNs. Thus, caution may be required in the interpretation of a normal TST result if severe LMN symptoms are present. Another explanation of normal TST ratios in ALS patients might be the occurrence of spinal synaptic reorganization,20 leading to a greater convergence of intact corticomotoneuronal axons onto resident motor neurons. Conversely, abnormal TST amplitude ratios were found in 27.3% of ALS patients without clinical UMN signs. This frequency is not markedly different from the 36% found in Rösler group of ALS patients who also showed abnormal TST ratios without UMN signs.5

Of the six patients with abnormal TST and no UMN signs in our study, two also showed increased RMTs. Although the TST ratios in those patients were relatively close to the normal level, the concurrent abnormality of RMTs and TST amplitude ratios suggested even in the absence of clinical UMN signs that the UMN system was involved. Confounding factors, such as proximal conduction blocks between the anterior horn cell soma and Erb point, were also excluded in ALS.5,21 These results may be explained instead by such a severe loss of proximal LMNs that the clinical examination of the upper arm is unable to detect a UMN involvement. These two patients later developed ALS, which indicates that the subclinical assessment of UMN involvement ultimately proved to be correct. Therefore, the probability of an ALS diagnosis apparently increases when a low TST amplitude ratio is detected. The use of TST is best suited to patients with minor UMN involvement, in whom a clinical neurological examination would have detected no abnormalities.

In contrast to previous studies of TST in ALS, this study included all patients referred to a motor neuron disease clinic. Many were ultimately diagnosed with central and peripheral neurological mimics of ALS, such as peripheral nerve or muscle disorders. A frequency of 12.5% abnormal TST amplitude ratios was found in these patients, which implies a high specificity of the TST test. Thus, most patients with peripheral abnormalities show a normal TST amplitude ratio.

As expected, the groups with various central motor disorders had a high percentage of abnormal TST results. In both ALS and non-ALS patients, an abnormal TST can be interpreted almost in the same way as clinical UMN signs. However, if other pathologies within the corticospinal system, such as cervical spondylotic myelopathy, are excluded by appropriate neuroimaging, then a low TST amplitude ratio increases the probability of ALS. Additional information can be gained from the CMCT that is more often abnormal in the case of compression.22,23 In this sense, TST deviations are not specific for ALS and can be used to find various central motor conduction abnormalities including those in multiple sclerosis and stroke.24

Resting motor threshold in ALS patients has been reported to be initially normal or reduced while increasing gradually with disease progression until the cortical response eventually disappears.25 Resting motor threshold has been studied less systematically. In our study, we found abnormal RMT values in 78.6% of ALS patients with UMN signs. This demonstrates that an abnormal RMT was frequently a measure for UMN dysfunction in our sample of ALS patients. Our results are in line with those of Triggs et al.,26 who found that RMT increases the sensitivity of TMS in ALS. The cause for increased RMT values in ALS is considered to be a progressive loss of functioning UMNs rather than a reduced corticospinal excitability.2 Hence, UMN loss in ALS may be more accurately diagnosed by the combined use of TST and RMT. This may be compared with the ratio of MEP/CMAPerb at rest, which in previous studies changed from one stimulus to the next5,17 and therefore suggests a lack of accuracy in the assessment of cortico-spinal impairments. In this study, the sensitivity of TST was with 89.3% higher than that of CMCT with 64.3%, again suggesting that CMCT is a less sensitive method for detecting UMN dysfunction in ALS.27

Besides its high sensitivity, the TST allows an estimation of the proportional loss of UMNs supplying the target muscle. Alternatively, Modified Ashworth Scale provides a unique clinical measure of spasticity that has been generally used to quantify the UMN involvement in stroke or multiple sclerosis.28,29 In this study, the Modified Ashworth Scale was found to be negatively correlated with the TST amplitude ratio in ALS patients, which suggests that the TST may reflect the severity of the UMN conduction failure. It was also found that decreased TST amplitude ratios are linearly correlated with increasing RMTs but the TST might be more sensitive than the RMT because in our patients with an RMT of 100%, the TST amplitude ratios ranged from 17% to 76%. In conclusion, the evidence discussed above suggests that TST may provide a quantitative electrophysiological measure of central motor conduction failure. This quantitative diagnostic method may therefore contribute to monitoring ALS disease progression in longitudinal studies, for which no alternative test exists to measure central nervous damage.30,31 Although TST is a potentially useful tool for monitoring disease progression in ALS patients, it needs to be further evaluated in follow-up studies.

It has been reported that testing several regions of the body increases the sensitivity of TMS to support an ALS diagnosis. Another study noted that the lower limb TST could improve the examination of corticospinal conduction failures in various diseases.32

We found that TST is neither painful nor time-consuming and is generally accepted by patients. However, there are two drawbacks of TST. First, this method cannot be used to study proximal muscles because the short time intervals of two stimuli prevent forming a clear separation between the first and second main deflection in TST curves. Second, for studying the lower limbs, the use of a monopolar needle electrode is required for gluteal stimulation, which can be explored in the future.33

In conclusion, TST appears to be an accurate and reliable measure for detecting and quantifying UMN conduction failure in ALS. Triple stimulation technique can contribute to an early diagnosis by finding subclinical evidence of UMN abnormality in suspected ALS. As a result, the level of diagnostic certainty in the evaluation of ALS may be increased.

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Amyotrophic lateral sclerosis; Transcranial magnetic stimulation; Triple stimulation technique; Upper motor neuron; Motor evoked potential

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