Normal parameters for diagnostic transcranial magnetic stimulation using a parabolic coil with biphasic pulse stimulation

Healthy Thai participants aged 20–60 years old were recruited from Maharaj Nakorn Chiang Mai Hospital, Thailand from November 2018 to June 2019. The following were the criteria for exclusion [5, 19, 24]:

The sample size was computed using N4Studies V1.4.1. From the formula, based on data from Garassus [21], we used CMCT from TA by the F-wave method, which is 10.7 ± 1.77 ms. The calculated size was equal to 43. We expected 20% to drop out. Therefore, this study planned to study 50 participants.

This study was a descriptive study design. All participants who passed the inclusion/exclusion criteria and had already signed the informed consent, received a single dose of diagnostic TMS. Before the intervention, blood pressure, heart rate, weight, height, arm, and leg length would be recorded. The arm length was measured from the right center of the axilla to the tip of the right middle finger while the patient was sitting in an upright position and fully abducted shoulder with elbow extension, wrist in a neutral position, and finger extension. The leg length was measured from the right anterior superior iliac spine (ASIS) to the right medial malleolus while the patient was supine. Any side effects that occurred during or after TMS would also be recorded. Participants could stop the intervention if they felt uncomfortable.

Transcranial magnetic stimulation (TMS). The MagPro® R30 with Option is manufactured by MagVenture® A/S Lucernemarken, 15 DK-3520, Farum, Denmark.

We used the MMC-140-II Parabolic Coil with power control as provided by Magventure. The coil has a parabolic shape, which makes contouring with the scalp easier and provides powerful and focused stimulation [22].

A trained physiatrist gave TMS at the left M1. The surface EMG electrodes were placed on the right abductor pollicis brevis (APB) and the right extensor digitorum brevis (EDB) muscles, respectively. We searched for the motor threshold (MT) which indicated the minimum intensity of the stimulation that induced an MEP greater than or equal to 50 µV for 5 out of 10 stimulations (a 50% successive trial) [4, 9].

The landmark for stimulation was C3 (the left M1). The hand motor areas were always on the left side of the leg areas, which were likely close to or at the vertex. We divided half the line, which measured from Nasion (Ns) to Inion (In). Then, we divided half the line that was measured from both tragi to find the vertex. The C3 hand motor area was 5 cm to the left of the vertex [4, 5, 27].

We used SPSS version 22.0 to analyze our data. The baseline characteristics of participants were evaluated. Outcome parameters were reported as mean and standard deviation (SD) or median and interquartile range (IQR), according to data distribution.

We screened a total of fifty-five healthy participants at Maharaj Nakorn Chiang Mai Hospital from November 2018 to June 2019. We excluded two participants with a history of carpal tunnel syndrome. We also excluded two participants with a history of seizures and one with a prior head injury. During the study, asymptomatic carpal tunnel syndrome from CMCT evaluation (prolonged distal latency of median nerve CMAP) was identified in two participants who were then excluded. Therefore, there were a total of forty-eight participants to analyze in our research, as shown in Fig. 2.

Baseline characteristics showed that all participants were equally distributed in each age group. They are both men, but mainly women. Weight, height, arm, and leg length were distributed in decrement patterns from a young age to an older age. As shown in Table 1, HADS-A, HADS-D, and TMSE showed normal cognitive function.

To compare the difference in MEP latencies and anthropometry, we divided our participants into two groups based on age (< 40 and ≥ 40 years old), height (< 160 and ≥ 160 cm), arm length (< 65 and ≥ 65 cm), and leg length (< 85 and ≥ 85 cm).

MT and MEPs could be easily obtained from APB for all participants. Unlike APB, EDB could be recorded in only 30 of 48 participants (62% of the total), whereas the rest (38% of the normal participants) were not able to be elicited despite using the intensity of more than 80% MSO (most of the subjects also reported discomfort). All reported data is shown in Table 2.

Using data from diagnostic TMS parameters acquired from the right APB and EDB, we investigated MEP latency differences across age, height, and arm and leg length (shown in Table 3).

Only three participants developed drowsiness, one had dizziness, and one had a mild headache after TMS sessions. All the TMS side effects disappeared in hours.

We measured that the MT of APB was 47.31 ± 8.06%. The value is slightly higher than data obtained from Rossini [4], 39–46%, and Triggs [20], 46.3 ± 7.2%. However, it is slightly lower than the MT recorded by Valls-Sole [29], 61.3 ± 9.6%. MT is variable in individuals for many reasons, such as relevant biological differences and sodium channel-blocking drugs that increase the resting MT [30]. The excitability of excitatory glutamatergic synapses, which connect the cortico-cortical fibers with the corticospinal neurons, also influences MT [31]. A more trivial factor relates to the inter-individual thickness of the convexity of the skull bones, which impacts the distance separating the stimulating coil from the excitable elements [32]. Another contributor is the number and density of cortico-cortical axons and corticospinal neurons in given target muscles [33].

The mean MT of EDB was 60.37 ± 8.74%. However, there is no reference to the mean MT of EDB in other studies. Therefore, we compare the MT of EDB in our study with that of other lower extremity muscles. We found that our data is at the lower normal limit but, corresponding to Rossini [4], the MT of TA was 60–80%.

We observed that the MT of EDB was higher than APB because the cortical homunculus of the foot is deeper than the hand [4, 5]. We always needed to increase coil intensity and adjust the coil medially and cephalad to the vertex from APB to EDB. However, we noticed that if we used MT with more than 80% MSO, most of the time patients felt uncomfortable, but no side effects were observed. Therefore, we had to cease the intervention before the MEP at EDB was elicited.

When we used the higher intensity, MEP latency was a bit shorter and the amplitude was much higher in comparison with MT, as shown in Table 2. However, the 120% MT could elicit an APB amplitude of MEP of more than 1 mV, which is accepted for use in most research [4, 5]. Therefore, we can use the APB latency and amplitude of MEP at 120% MT for diagnosis. However, be aware that 140% MT may provide better optimal conduction due to the larger amplitude of supramaximal stimulation. The median of MEP amplitude at 120% and 140% MT were 1.04 (0.80–1.68) and 2.24 (1.47–3.52) mV, respectively.

We usually observed higher MEP amplitude when increasing %MSO, which can be explained by stimulus–response curves [7] and also with preactivated muscle contraction. We found that MEP amplitudes obtained from previous studies use a high MSO, i.e., 70% and 85% [19], and 100% [18]. Some employed slight voluntary contraction, i.e., 15–25% of maximum [19], and more than 20% of maximum [21], which may be explained by alpha motoneuron preactivation [18]. However, we used the resting MEP with higher power requirements to reach the I3 wave and cause neuronal discharge [18]. This reason may explain why our MEP amplitudes were low between 1 and 2 mV but in an optimal range [2].

According to the study of the stimulus–response curve, TMS stimulus intensity and MEP amplitude share a relationship. This relationship shows a correspondence between MEP ranging from 120 to 140% MT [34]. Therefore, this stimulus–response relationship can be studied by calculation of the amplitude ratio of the MEPs obtained at 140% and 120% MT [4]. The ratio of 140/120 MEP would help us measure cortical excitability. The median 140/120 MEP ratio was 1.92 (1.45–2.81), which is nearly two-fold. If there is too much or too little deviation from this amount, one should be cautious of an abnormal response from the corticospinal network. Keep in mind that deprivation of sleep, caffeine, and other stress may aggravate many responses as well [35, 36].

In contrast to EDB, 120% MT could not elicit the MEP amplitude of EDB by more than 1 mV [0.60 (0.38–0.98) mV]. However, when we increased to 140% MT, the amplitude was nearly 1 mV [0.95 (0.69–1.55) mV]. As a result, the optimal intensity for diagnosis should be 140% of MT when recorded at EDB. The 140/120 MEP ratio of EDB is also nearly two-fold [1.74 (1.25–2.14) mV] as well, corresponding to the upper limb-APB recording.

However, in clinical practice, the single best-trial MEP with the largest amplitude is more suitable for use for analysis as this MEP reflects the optimal corticomotor conduction. Contrary to scientific TMS studies on corticospinal excitability, it may not be necessary to analyze or estimate the amplitude of all recorded MEPs for diagnostic TMS [5].

The method that we used for CMCT is the F-wave method. Our APB CMCT latency (7.81 ± 1.32 ms at 120% and 7.19 ± 1.21 ms at 140% MT) is nearly identical to Livingston [37], 7.8 ± 0.2 ms, and Eisen [19], 7.10 ± 2.0 ms, a tad longer than Furby [18] 6.1 ± 1.0 ms, and Claus [11] 5.8 ± 0.8 ms, and significantly longer than Rossini [38], 5.66 ± 0.84 ms in 16–35 years old and 5.45 ± 0.72 ms in 51–86 years old. CMCT discrepancies might be owing to differences in biological parameters, medicines, caffeine, sleep, and other external stress factors that may influence its outcome, regardless of coil type or stimulation power.

If there was no peripheral disease, CMCT calculated using the F-wave gives a shorter (1–1.5 ms) direct root stimulation with greater accuracy [4]. This could be due to the stimulation point to stimulate the nerve root being further away from the spinal motoneurons, e.g., 4 cm lateral to the spinal motoneurons [18]. The proximal root segment is therefore left between the cord and the exit foramen [7, 18]. As a result, the F-wave approach underrates CMCT and the longest F-wave should be employed [7]. However, both methodologies can provide the same results when it comes to estimating the place where motor fibers are depolarized by magnetic spinal stimulation [21].

The CMCT from EDB (14.33 ± 2.50 ms at 120% and 13.63 ± 2.57 ms at 140% MT) in our study are the same as Furby [18], 14.3 ms in males, and Stephan [39], 14.6 ± 2.9 ms. but slightly longer than Eisen [19], 13.1 ± 3.8 ms. Again, this disparity might be due to a variety of biological and environmental causes.

TMS penetration depth is restricted because dispersion increases exponentially with the proximity of the coil. TMS is effective at low stimulus levels in the M1-hand area, whereas greater intensities are required in the M1-leg area [5]. We calculated CMCT by using both 120% and 140% MT latencies. Both values were slightly different. According to optimal intensity, we propose utilizing 120% MT for APB and 140% MT for EDB. In other words, 120% MT is sufficient for the upper limb, whilst 140% MT is more suitable for the lower limb.

ICF represents the excitatory glutaminergic function in M1 by using CS and TS [2]. This value has not been previously reported. The paired-pulse stimulation with ISI at 10 ms can increase the amplitude abruptly by twofold of the MEP amplitude at 120% MT of both APB and EDB [ratio = 2.18 (1.45–3.20) and 1.70 (1.52–2.30), respectively]. This value helps to confirm the excitatory function of the cortex after single-pulse TMS. Furthermore, ICF helps to diagnose CNS diseases, such as patients with cerebellar diseases who have reduced ICF response. In contrast, patients with dystonia had an increased ICF response [7].

SICI is represented by post-synaptic inhibition mediated by GABA-A receptors [2]. Again, we are the first to report this value. The paired-pulse stimulation with ISI at 2 ms can decrease MEP amplitude at 120% MT for abruptly ¼-fold of both APB and EDB [ratios = 0.24 (0.12–0.51) and 0.24 (0.15–0.41), respectively]. These values help to evaluate the suppression function of cortical networks and CNS disease diagnosis. For example, patients with amyotrophic lateral sclerosis (ALS) or movement disorders have a reduced SICI response due to impaired inhibitory function [7]. Again, some machines could not produce paired-pulse stimulation.

Both ICF and SICI paired-pulse stimulations are useful in selecting the most appropriate medication for a patient by matching the identified abnormality of cortical facilitation or inhibition with the effects of various pharmaceutical agents [2]. In our setting, the paired-pulse stimulations, distinct from single-pulse, help physicians evaluate the hypo- or hyper-excitatory function of the hemisphere. Then, physicians can select the proper mode of therapeutic TMS for a patient based on cortical function.

As certain devices are incapable of delivering paired-pulse stimulation, other metrics from a single pulse, such as MT, MEP, 140/120 MEP ratio, and SP, cannot be directly substituted for this number because they indicate distinct electrophysiological processes and neurochemical consequences [40, 41].

The SP represents inhibitory mechanisms in the motor cortex which are most likely mediated by GABA-B receptors [2]. According to our findings, the SP from APB and EDB were 121.58 ± 21.50 and 181.01 ± 40.99 ms, respectively. These numbers are allied with Rossini [2, 4], whose SP from APB was approximately 100–300 ms. This suppression mechanism helps to confirm normal cortical excitability as well.

Furthermore, SP abnormality is beneficial for CNS diagnosis. For example, patients with acute stroke have a long duration of SP. In contrast, patients with ALS often have a short duration of SP due to intracortical inhibitory impairment [2]. This finding provides the pathophysiology of diseases and a treatment plan. Every TMS machine that has EMG monitoring could be able to record this value. However, we could not find any reference numbers from EDB. Thus, this is the first study to report the normal value of SP from EDB.

We found a difference in MEP latencies of APB between height groups (< 160 and ≥ 160 cm) at 120% MT [21.02 ± 1.25 and 22.45 ± 1.32, t(46) = -3.86, p < 0.001], and also at 140% MT [20.33 ± 1.04 and 21.94 ± 1.33, t(46) = -4.65, p < 0.001]. The moderate correlation between height and MEP latencies of APB at 120% and 140% MT (r = 0.38 and 0.51, respectively) is shown in Figs. 3 and 4.

We also discovered only a difference in MEP latencies of APB between arm-length groups (< 65 and ≥ 65 cm) at 120% MT [21.29 ± 1.31 and 22.24 ± 1.48, t(46) = -2.36, p = 0.022] and 140% MT [20.56 ± 1.24 and 21.77 ± 1.39, t(46) = -3.20, p = 0.002]. However, there were no MEP latency differences in EDB between height groups and leg length groups. We could also elicit MEP of EDB for only 60% of participants. These findings are compatible with Eisen [19] who found a high relationship between arm length and thenar MEP latency (r = 0.65). But there was no correlation between TA latency and height. However, some studies found only a positive relationship between height and CMCT to the lumbosacral region. As a result, CMCT to upper limb muscles had no or only a slight relationship with height, but CMCT to lumbar segments had a substantial correlation with height [7, 11, 18]. These findings may suggest that the deeper the homunculus for the leg area, the more difficult it may be to elicit MEP of EDB. Also, the power may not be enough to show the relationship between MEP latencies of EDBs in height and leg length.

As the height and arm length should be in linear proportion [42], we then compared the relationship between height and arm length and also found a high positive correlation between them (r = 0.756), as shown in Fig. 5. Therefore, we can select either height or arm length for anthropometric measurement to evaluate APB latencies.

There were no MEP latency differences between APB and EDB between age groups, as shown in Table 3. Age and sex have negligible effects on the MEP measures. The study of Groppa [5] also found that CMCT showed no significant age effect on stimulus intensity even if the intensity was high enough, unlike the cortical motor threshold and MEP amplitudes, which slightly changed with increasing age. This corresponds to the study by Chen [7], which found no or only a slight association with age.

Regarding sex, the study by Livingston [37], after adjusting MEP latencies to participants’ limb length, found no significant differences between males and females; only upper and lower limb lengths correlate with MEP latencies [7, 23]. However, there are only a few studies that contradict these results, which found a gender difference in the leg CMCT after controlling for differences in age and height [7, 23]. The reason for such a difference remains unclear and may be explained by the different methods used between the studies. Also, Akilan [43] attempted to explain the disparity between the RMT as measured by TMS and cognitive function, i.e., MMSE and RBANS scores. However, we found no difference in the mean RMT as 46.06 ± 7.81 in males and 49.96 ± 11.16 SD in females, which are in the normal range as mentioned in our study, 44.31 ± 8.06. Abnormal values are defined as being 2 or more conservatively as 2.5 standard deviations (SD) from the data's mean. At least this is negligible enough to interpret the difference between males and females.

Unlike other therapeutic TMS reported in the last updated review [44], the side effects of diagnostic TMS seem to be less common. As allied to the study by Furby, there were no unwanted side effects from 50 participants [18]. Only a few participants in our study experienced tolerable transient side effects that resolved quickly after the TMS session. The reason may be explained by the amount and frequency of stimulation. Currently, diagnostic TMS uses only a few hundred pulses, which have a pause duration between each pulse for a few seconds, compared with a few thousand pulses with up to 50 pulses for theta-burst stimulation for a treatment session. Therefore, we can conclude that diagnostic TMS is safe and did not show serious side effects among the participants [3].

EDB required more effort to elicit because the cortical homunculus of the foot is deeper than that of the hand. Only 30 participants could elicit an EDB. Therefore, this sample size might not be enough to show the effect of leg length on EDB latency. In future research, other muscles of the lower extremity might be selected for recording to find normal parameters. Also, it is cautioned that in the normal population, some individuals could not elicit the EDB.

Our participants were 20 to 60 years old. Therefore, the normal values of our study could not be compared with the parameters of patients less than 20 or more than 60 years old.

We chose the right APB and EDB from each participant as representative of the left corticospinal tract due to their ease of use and representation of the dominant side of the hemisphere. The left APB and EDB from the right cerebral hemisphere were not recorded in this study. Therefore, inter-side differences could not be assessed due to the lack of bilateral recording.

The rightward shift of the stimulus–response curve could be present due to the shorter duration of each stimulation [4]. We recognized that the longer duration, i.e., 20 s [28], is the best to ensure that the hysteresis effects would not have occurred. The shorter time interval may be suitable for the clinician in real-world practice.