|Year : 2021 | Volume
| Issue : 2 | Page : 90-96
Normative Values of Transcranial Magnetic Stimulation-Evoked Parameters for Healthy Developing Children and Adolescents
Hasan Tekgul1, Ulas Saz2, Muzaffer Polat1, Nurdan Tekgul3, Timur Kose4
1 Department of Pediatrics, Division of Child Neurology, Faculty of Medicine, Ege University, Izmir, Turkey
2 Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
3 Adolescents Health Center, Clinic of Family Medicine, Tepecik Training and Research Hospital, Izmir University of Health Sciences, Izmir, Turkey
4 Department of Biostatistics, Faculty of Medicine, Ege University, Izmir, Turkey
|Date of Submission||04-Jul-2020|
|Date of Decision||19-Sep-2020|
|Date of Acceptance||24-Jan-2021|
|Date of Web Publication||15-Jun-2021|
Department of Pediatrics, Division of Child Neurology, Faculty of Medicine, Ege University, Izmir
Source of Support: None, Conflict of Interest: None
Context: Normative data-containing transcranial magnetic stimulation (TMS) evoked parameters are essential for correctly interpreting healthy development and assessing neuroplastic changes in certain neurologic disorders. Aims: The aim is to investigate corticospinal pathways by applying TMS to healthy developing children and adolescents. Settings and Design: In this cross-sectional study, we measured TMS evoked parameters associated with cortical and spinal stimulation obtained from the four extremities of 46 healthy children and adolescents (21 boys and 25 girls; mean ± standard deviation age: 6.4 ± 1.2 years; range: 3.0–20.5 years). Statistical Analysis: Spearman's correlation coefficients were calculated for each variable (weight and height) as a function of motor evoked potential (MEP) response latency and central motor conduction time (CMCT). Pearson's Chi-square test was used to determine the inter-variable correlations. Results: Latencies of MEPs were correlated with age (P < 0.001, r = 0.6948) and height (P < 0.006, r = 0.7994). Amplitudes of active-state MEPs were significantly higher than those of resting-state MEPs associated with the upper and lower extremities. The mean values for active-state MEP latencies were lower than those for resting-state MEPs. The CMCT and magnitudes of latency jumps were calculated using reliable MEP data for children and adolescents. Additionally, the unresponsiveness rates were significantly higher for children aged below 7 years. Conclusion: The TMS evoked parameters investigated in this study are necessary to accurately assess corticospinal pathway development in healthy children and adolescents.
Keywords: iCentral motor conduction time, corticospinal pathways, latency jumping, motor evoked potentials, transcranial magnetic stimulation
|How to cite this article:|
Tekgul H, Saz U, Polat M, Tekgul N, Kose T. Normative Values of Transcranial Magnetic Stimulation-Evoked Parameters for Healthy Developing Children and Adolescents. Neurol Sci Neurophysiol 2021;38:90-6
|How to cite this URL:|
Tekgul H, Saz U, Polat M, Tekgul N, Kose T. Normative Values of Transcranial Magnetic Stimulation-Evoked Parameters for Healthy Developing Children and Adolescents. Neurol Sci Neurophysiol [serial online] 2021 [cited 2021 Sep 18];38:90-6. Available from: http://www.nsnjournal.org/text.asp?2021/38/2/90/318503
| Introduction|| |
Transcranial magnetic stimulation (TMS) has shown promise as a tool for diagnosing, monitoring and treating various neurologic and psychiatric diseases in adults.,,, Conversely, the potential of TMS has not yet been comprehensively explored regarding its use in children. However, TMS offers a unique opportunity to gain new insight into the motor system, and it may prove to be a useful tool in the investigation of healthy development, developmental disabilities, and degenerative diseases.,,, TMS also possesses the potential to assess the therapeutic effects of treatments for certain neurologic disorders.
A large number of studies have focused on the use of TMS in examining the motor cortical function and the corticospinal pathway by analyzing various TMS evoked parameters, i.e., motor evoked potentials (MEPs), central motor conduction time (CMCT), and the magnitude of latency jumps.,,, Most studies focused on a single disorder; however, a few took into account the age-related changes in the TMS evoked parameters for normally developing children and adolescents. As an example, a recent article provided normative value data for the lower limbs. Studies should emphasize the importance of using normative TMS evoked parameter data to correctly interpret healthy development and certain neurologic disorders.,,, To this end, this study aimed to investigate the corticospinal pathways by analyzing various TMS evoked parameters, i.e., MEPs, CMCTs, and latency jump magnitudes in healthy developing children and adolescents.
| Materials and Methods|| |
A total of 46 healthy children and adolescents (21 boys, 25 girls; mean ± standard deviation [SD] age: 6.4 ± 1.2 years; range: 3.0–20.5 years) were included in the study. None of the subjects had a previous history of neurologic illness or were taking medication at the time of the survey. The study was approved by the Ege University Hospital ethics committee. Informed consent for participants aged <18 years was obtained from the legal guardian, whereas it was directly obtained from participants aged 18 and over.
Transcranial magnetic stimulation
Various TMS evoked parameters, i.e., MEPs, CMCTs, and latency jump magnitudes were investigated by applying contralateral and ipsilateral cortical stimulation (ILCS) for specific upper and lower extremity muscles. To study corticospinal pathway characteristics, single-pulse TMS was delivered via a circular magnetic coil that was connected to Medelec devices. In this study, we used a circular coil (Novometrix Magstim 200, 2 Tesla version, Whitland, Dyfed, Wales, UK) with the potential to simultaneously stimulate both cerebral hemispheres.
The children were positioned on a bed with their heads fixed in a plastic foam headrest. A circular magnetic coil was tangentially applied over the vertex region to obtain MEPs associated with arm muscles. The motor cortex was stimulated with a circular coil that was tangentially centered approximately 2–4 cm lateral to Cz (range, 2–8 cm) and 2–3 cm in the anterior direction.,, The suggested point of stimulation, i.e., 7 cm anterior and 2–4 cm lateral to the Cz point, was applied to obtain MEPs associated with leg muscles. Electromyography electrodes were placed on the thenar eminence and tibialis anterior muscle. If MEPs were not observed, the coil was adjusted along the sagittal plane, roughly perpendicular to the assumed line of the central sulcus.
The resting (r) and active periods (a) for the four extremities were investigated for all subjects. During the active period, the subject grasped a spherical reflex hammer to stimulate the motor cortex. MEPs were recorded during the grasping period. TMS obtained four to 16 MEPs from each stimulation site [Figure 1]. Four TMS parameters were measured for each child: (1) MEP latency, (2) MEP amplitude, (3) CMCT, and (4) latency jump magnitude. A “no response” was defined as the absence of an MEP that met the amplitude criterion (e.g., a 5-μV peak-to-peak amplitude) for five of 10 trials under the condition of optimal placement of the coil over the motor cortex, and the maximal stimulation level (i.e., 90% of maximum TMS voltage).
|Figure 1: A 9-year-old healthy girl. Transcranial magnetic stimulation evoked motor evoked potential with contralateral cortical stimulation obtained from anterior tibialis muscle during the active state|
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The CMCT was determined using the equation (CMCT = cortical MEP latency-radicular spinal MEP latency), based on reliable cortical and radicular MEPs.,, The latency jump was determined using the following equation: (resting cortical MEP latency-active cortical MEP latency). Reliable cortical MEPs evoked during the resting and active periods were used to calculate CMCT and latency jumping.
Statistical analysis was performed to compare the subgroups of healthy children. For the paired-group analysis, one-way analysis of variance was used. For the between-group comparisons, a Pearson's Chi-square test was used to determine the inter-variable correlations. Spearman's correlation coefficients were calculated for each variable (weight and height) as a function of MEP response latency and CMCT.
| Results|| |
Transcranial magnetic stimulation-evoked motor evoked potential responses
TMS-evoked MEP responses were obtained by applying contralateral cortical stimulation (CLCS) and ILCS to stimulate the four extremities. TMS may fail to evoke an MEP response in children aged under 4 years for the upper limbs and those under 8 years of age for the lower limbs. For this reason, we investigated resting-and active-state TMS-evoked MEP responses [Figure 2].
|Figure 2: A 13-year-old boy. Transcranial magnetic stimulation evoked normal motor evoked potential with contralateral cortical stimulation obtained from right thenar muscles during the active state (F), and during the resting period (I). Note the shortened latency and increased amplitude during the active state|
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Upper-extremity motor evoked potential responses to contralateral cortical stimulation
The mean MEP amplitude values obtained during the active state experiment, which involved right cortical (mean ± SD: 1.73 ± 1.28 mV) and left cortical stimulation (mean ± SD: 1.85 ± 1.95 mV), were significantly higher than those associated with right cortical (mean ± SD: 0.80 ± 0.67 mV) and left cortical stimulation (mean ± SD = 1.09 ± 0.94) during the resting period (P < 0.05) [Table 1]. The mean resting-state MEP latency values associated with right cortical (mean ± SD: 20.70 ± 3.80 ms) and left cortical stimulation (mean ± SD: 19.56. ± 3.17 ms) were found to be significantly higher (P > 0.05) than the corresponding active-state values for right cortical (mean ± SD: 16.95 ± 4.13 ms) and left cortical stimulation (mean ± SD: 17.60 ± 6.3.29 ms) application for the target upper extremity muscle (i.e., the thenar muscle).
|Table 1: The latency and amplitude of transcranial magnetic stimulation evoked motor evoked potentials during the resting period and at the active state in healthy developing children and adolescents (n=46, mean±standard deviation age: 6.4 1.2 years; range, 3.0-20.5 years)|
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Lower-extremity motor evoked potential responses to contralateral cortical stimulation
The mean MEP amplitude values obtained during active facilitation and simultaneous right cortical (mean ± SD: 0.69 ± 0.49 mV) and left cortical stimulation (mean ± SD: 0.54 ± 0.42 mV) were significantly higher (P < 0.05) than those associated with resting-state right cortical (mean ± SD: 0.43 ± 0.47 mV) and left cortical stimulation (mean ± SD: 0.39 ± 0.44 mV) during the resting period [Table 1]. The mean resting-state MEP latency values associated with right cortical (mean ± SD: 26.20 ± 4.60 ms) and left cortical stimulation (28.20 ± 6.58 ms) were higher than the corresponding active-state values for right cortical (mean ± SD: 23.92 ± 4.75 ms) and left cortical stimulation (mean ± SD: 25.88 ± 6.39 ms) for the target lower extremity muscle (i.e., the tibialis anterior muscle).
Upper-and Lower-Extremity motor evoked potential responses to spinal stimulation
The mean resting-state MEP latency values obtained during cervical spinal stimulation (mean ± SD: 10.02 ± 1.61 ms) were higher than those obtained during active facilitation (mean ± SD: 9.72 ± 1.87 ms) of the target upper extremity muscles (i.e., the thenar muscles), with P = 0.051. The resting-state MEP latency values obtained during lumbar spinal stimulation (mean ± SD: 9.13 ± 2.18 ms) were higher than those obtained during active facilitation (mean ± SD: 9.04 ± 2.27) of the target lower extremity muscle (i.e., the tibialis anterior muscle), with P = 0.055 [Figure 3] and [Table 1]. In addition, a comparison of the TMS-evoked MEP amplitude values revealed that the active-state amplitude values were higher; however, no statistical significance was found (P > 0.05).
|Figure 3: A 16-month-old boy. Transcranial magnetic stimulation evoked normal motor evoked potential with lumber stimulation obtained from right thenar muscles during the resting period (I), and an active state (F). Note the shortened latency and increased amplitude during the active state|
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Transcranial magnetic stimulation-evoked motor evoked potential responses to contralateral cortical stimulation and ipsilateral cortical stimulation
The active-state MEP responses to CLCS, ILCS, and cervical and lumbar spinal stimulation are given in [Table 2]. MEP latencies and amplitudes associated with TMS application to the right and left contralateral cortex were compared to evaluate cerebral dominance and disparity between the left and right sides. There was no statistical difference between the groups that suggested left-and right-side disparity (P > 0.05).
|Table 2: The latency and amplitude of transcranial magnetic stimulation-evoked motor evoked potentials at the active state in healthy developing children and adolescents (n=46, mean±standard deviation age: 6.4±1.2 years range, 3.0-15 years)|
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Unresponsiveness rate of motor evoked potential responses
The unresponsiveness rates for healthy children who received TMS during resting and active periods were studied. The results were divided into two groups (Group I: Children younger than 7 years, Group II: Children older than 7 years), as presented in [Table 3]. The resting-and active-state unresponsiveness rates during right and left cortical stimulation were significantly higher for Group I. During the resting period, cortical TMS failed to evoke upper- and lower-extremity MEP responses in 3.5%–4.5% and 40%–56% of Group II children, respectively. By contrast, cortical TMS failed to evoke upper- and lower-extremity MEPs in 60%–67.5% and 80%–87.58% of Group I children, respectively. Conversely, TMS-evoked MEP responses to spinal stimulation were obtained from all children.
|Table 3: Unresponsiveness rate of transcranial magnetic stimulation-evoked motor evoked potential potentials during the resting period in healthy developing children and adolescents|
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Correlation of motor evoked potential responses with age and height
The active-state cortical TMS-evoked MEP latencies for the upper and lower extremities were correlated with age (P < 0.001, r = 0.695) [Figure 4] and height (P < 0.006, r = 0.799). In addition, a significant correlation was found between age and MEP amplitudes associated with the right and left thenar muscles (P < 0.001).
|Figure 4: The latencies of active motor evoked potentials evoked with cortical transcranial magnetic stimulation on the right thenar muscles were correlated with age (P < 0.001, r = 0.6948)|
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Central motor conduction time and latency jumps
The latency of a TMS-evoked MEP response can be used to estimate the CMCT. In this study, the following equation was used: Cortical MEP latency – spinal MEP latency. Reliable cortical and radicular MEPs were required to calculate the CMCTs and magnitudes of latency jumps (n = 41 for CMCT, and n = 39 for latency jumps). The CMCT calculations were performed by using the active-state MEP data. The magnitudes of latency jumps were determined by calculating the difference between resting-and active-state MEP latencies. The mean active-state upper-extremity CMCT values for the right and left sides were calculated to be as follows: 7.01 ± 3.8 ms, and 7.60 ± 3.2 ms, respectively. The mean upper-extremity magnitudes of latency jumps were calculated as 3.07 ± 2.46 ms and 1.85 ± 2.27 ms for the right and left sides, respectively [Table 4].
|Table 4: Multinomial logistic regression analysis with subgroups as a dependent variable|
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| Discussion|| |
TMS is a useful neurophysiologic tool for the assessment of the corticospinal pathways in children and adolescents. In particular, it can be used to functionally evaluate the maturation of the brains of healthy children of different age groups.,, In this study, we tested the applicability and value of administering TMS to healthy developing children. This study represents the first to obtain normative data for various TMS-evoked parameters (i.e., MEP latency and amplitude, CMCT, and latency jump magnitude) for healthy developing Turkish children and adolescents. This study also evaluated age-related changes in the corticospinal neurophysiology of the proximal and distal upper extremity muscles in healthy children and demonstrated differences in the maturational changes of this motor pathway for each muscle.
Previous TMS studies reported a high correlation between age and TMS-evoked MEP latency and amplitude in children.,,, In addition, Eisen et al. showed a prolonged MEP latency and decrease in upper- and lower-extremity MEP amplitude with age. In a Korean study, Yook et al. also reported the age-related changes in the proximal and distal upper extremity muscles in healthy children. They demonstrated differences in the maturational changes of this motor pathway for each muscle. In the present stıudy, we found that the latencies of upper- and lower-extremity TMS-evoked MEPs were highly correlated with age and height. The values of MEP latencies with cortical stimulations are similar to the Korean values.
Strong relationships between maturation and MEP latency and amplitude were observed in our study, and in other previous pediatric studies.,,, Corticospinal tract myelination is known to end at approximately 3–5 years of age. The transmission speed of the descending motor pathways, as determined by MEP registration, reaches adult values between the ages of 10 and 12 years. To detect age-related changes in children, Koh and Eyre first obtained MEP amplitudes from healthy children at different stages of development. They showed that the transmission speed in the descending motor pathways progressively increased with age, reaching adult values approximately at the age of 11 years.
TMS-evoked MEPs could be elicited from all age groups of children. However, it is difficult to obtain a resting-state MEP response to TMS for the upper and lower extremities in children aged under 7 years.,,, In this study, in the case of the Group II children (i.e., children aged over 7 years), resting-state cortical TMS failed to evoke upper-and lower-extremity MEPs in 3.5%–4.5% and 40%–56% of trials, respectively. By contrast, in Group I children (i.e., children aged under 7 years), resting-state TMS failed to evoke MEPs in 60%–67.5% and 80%–87.5% of the upper and lower extremity trials, respectively. Similar unresponsiveness rates have been reported for two TMS studies involving children under 8 years.,, This study also observed a reduced unresponsiveness rate (2.1%) with cortical TMS in children and adolescents during active facilitation. In addition, spinal TMS (i.e., cervical and lumbar) evoked MEP responses in healthy children age groups. These findings support the hypothesis that peripheral nervous system maturation occurs before central nervous system maturation.
We also found statistically significant differences in MEP latency and amplitude results obtained during the resting and active periods. Specifically, active-state MEP latency values were lower than those associated with the resting period. Conversely, the active-state MEP amplitudes were larger than those associated with resting. These findings are consistent with those reported in previous studies., Moreover, Caramia et al. reported a gradual decrease in resting-and active-state MEP latency with age. We observed no disparity between the left and right sides in terms of MEP latency, MEP amplitude, and CMCT for the upper or lower extremities; this finding is consistent with the results reported in two previous studies.,
Motor cortical TMS may evoke an MEP response in the homologous target muscle ipsilateral to the stimulus. These MEPs are known to indicate the presence of motor projections from the motor cortex to the corticospinal pathways in healthy persons. They may also mediate the increased participation of the less affected hemisphere after a cortical injury in a developing brain., These normative results may facilitate the analysis of developmental neuroplastic changes that occur in children with hemiparesis.
TMS-evoked MEP latency can be used to estimate CMCTs. The CMCT developmental pattern reaches maturity in children within the first 3–5 years of postnatal life. However, the resting-state CMCT does not reach maturity until early adolescence., In addition, the magnitude of latency jumps in preschool children has been reported to be four times larger than that in adults; furthermore, it gradually decreases until mid-adolescence is reached. The mechanisms responsible for this gradual decrease remain to be unclear.
In this study, we defined the mean CMCT and latency jump magnitude values for healthy developing children and adolescents. However, in a recently published study, we used a normative dataset, which included TMS-evoked MEPs, CMCTs, and latency jump magnitudes, to calculate the Z-scores of the parameters obtained from children with cerebral palsy. To normalize MEP latency data and negate height differences among the age-matched subjects, the active-state MEPs were corrected by calculating the Z-score (i.e., [observed value − expected value]/SD). It should be noted that the SD of the normal group was implemented as the SD. Thus, Z-scores lower than 2.5 (no response) or higher than 2.5 (extended latency) were considered to be abnormal.
The number of healthy children who participated in this study was relatively small and thus was a limitation of this TMS study. Specifically, the amount of normative data for each age group was not sufficiently large. Subgroup analysis based on each age group could not be performed because of the limited numbers of the study population. The group averages between two groups <7 years of age versus >7 years of age) are highly reliable. However, the first study was related to normative values in the Turkish healthy children population with modest sample size. Each subject was investigated with TMS of the four extremities. The study provided the normal limits of variability in the four TMS parameters for a considerable number of healthy children and adolescents in a pediatric neurophysiology laboratory.
| Conclusions|| |
Various TMS evoked parameters, including the MEP, CMCT, and latency jump magnitude, are necessary to accurately assess corticospinal pathway development in healthy developing children and adolescents. This study demonstrated that the above-mentioned TMS evoked parameters are strongly related to the age and height of healthy controls. Furthermore, normative TMS evoked parameter data are essential for the correct interpretation of healthy development, as well as an accurate comparison of certain neurologic disorders.
An informed consent form approving the use of patient information and material for scientific purposes was signed by the parents of the patient.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]