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. 2017 Apr 5;118(1):140–148. doi: 10.1152/jn.00076.2017

Developmental profile of motor cortex transcallosal inhibition in children and adolescents

Patrick Ciechanski 1, Ephrem Zewdie 1, Adam Kirton 1,2,✉
PMCID: PMC5494372  PMID: 28381485

Here we demonstrate that transcranial magnetic stimulation can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, handedness, and motor performance. Interestingly, we also demonstrated sex effects, possibly related to the differing developmental profiles of boys and girls. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy.

Keywords: TMS, pediatrics, transcallosal inhibition

Abstract

Transcallosal fibers facilitate interhemispheric networks involved in motor tasks. Despite their clinical relevance, interhemispheric motor control systems have not been completely defined in the developing brain. The objective of this study was to examine the developmental profile of transcallosal inhibition in healthy children and adolescents. Nineteen typically developing right-handed participants were recruited. Two transcranial magnetic stimulation (TMS) paradigms assessed transcallosal inhibition: ipsilateral silent periods (iSP) and paired-pulse interhemispheric inhibition (IHI). TMS was applied to the motor hotspot of the first dorsal interosseous muscle. Resting motor threshold (RMT), iSP latency, duration and suppression strength, and paired-pulse IHI were measured from both hemispheres. The Purdue Pegboard Test assessed unimanual motor function. Hemispheric differences were evident for RMT and iSP latency and suppression strength, where the left hemisphere had a lower RMT, prolonged latency, and greater suppression strength. iSP duration showed hemispheric symmetry. RMT and iSP latency decreased with age, whereas iSP suppression strength increased. Girls showed shorter iSP latency. Children typically displayed IHI, although hemispheric differences were observed. iSP suppression strength was uniquely associated with IHI within individuals. iSP duration correlated with motor performance. TMS can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, sex, and motor performance. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy.

NEW & NOTEWORTHY Here we demonstrate that transcranial magnetic stimulation can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, handedness, and motor performance. Interestingly, we also demonstrated sex effects, possibly related to the differing developmental profiles of boys and girls. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy.

transcallosal fibers facilitate interhemispheric functional networks. Excitatory neurons from layer III of the primary motor cortex (M1) project across the corpus callosum and are thought to synapse on inhibitory interneurons in the contralateral layer V (Jones et al. 1979; Meyer et al. 1995, 1998). Generating muscle force for unilateral hand movement requires timed inhibition of the ipsilateral hemisphere (Ferbert et al. 1992; Liepert et al. 2001; Newton et al. 2005), which may be mediated through these transcallosal pathways. Dexterity of the hand may also be related to the integrity and development of these pathways, suggested by correlations of higher motor performance with increased callosal thickness (Kurth et al. 2013). Conversely, decreases in motor function, such as those following stroke, may be related to an imbalance of transcallosal inhibition. Evidence suggests that following subcortical stroke, there is a shift in transcallosal inhibition, such that the nonlesioned hemisphere exerts a greater degree of inhibition on the lesioned hemisphere (Murase et al. 2004) with severity of motor impairment linked to the magnitude of this shift.

Transcranial magnetic stimulation (TMS) facilitates the direct, in vivo study of interhemispheric motor neurophysiology. By stimulating M1, activating distal muscles of the upper extremity and recording muscle EMG, TMS can probe motor network functional connectivity. Two TMS techniques commonly used to study transcallosal inhibition are ipsilateral silent periods (iSP) and paired-pulse interhemispheric inhibition (IHI). Production of an iSP requires stimulating M1 while contracting the ipsilateral hand, resulting in the transient suppression of voluntary motor activity (Wassermann et al. 1991). The mechanisms of iSP appear to involve transcallosal inhibition (Heinen et al. 1998; Meyer et al. 1995, 1998). Conversely, IHI TMS paradigms involve directly stimulating M1 in both hemispheres with the hands at rest. A conditioning stimulus applied to one M1 immediately before a test stimulus applied to the contralateral M1 results in inhibition of the motor evoked potential (MEP) induced by the latter. Varying the interstimulus interval between conditioning and test stimuli has defined both short (e.g., 8–10 ms) and long (e.g., 40–50 ms) interval forms of IHI (Ni et al. 2009). Despite suggested common mechanisms, direct comparisons of IHI and iSP have been limited (Chen et al. 2003) and have never been performed in the developing brain.

Transcallosal inhibition has been described in detail in healthy adults (Chen et al. 2003; Ferbert et al. 1992) but incompletely investigated in the pediatric brain (Mayston et al. 1999). Limited evidence suggests that components of the iSP such as latency and duration may mature with age (Garvey et al. 2003, 2005). These changes in ipsilateral inhibition are clinically relevant, associated with the development of simple motor skills such as finger tapping (Garvey et al. 2003). As noninvasive brain stimulation applications in pediatrics are refined from existing protocols (Rajapakse and Kirton 2013), currently based on adult evidence, it is necessary to describe typical neurophysiological development to ensure optimal montages and parameters are used.

Therapeutic noninvasive brain stimulation technologies, such as transcranial direct-current stimulation and repetitive TMS, are increasingly applied in stroke rehabilitation to improve motor function of a paretic limb (Elsner et al. 2013; Hsu et al. 2012; Lefaucheur et al. 2014). The majority of trials to date have been based on the premise of imbalanced transcallosal inhibition with neuromodulation aiming to shift this balance toward normal, either by increasing excitability of the lesioned M1, decreasing the excitability of the nonlesioned M1, or a combination of both (Fregni and Pascual-Leone 2007). Preliminary evidence from childhood stroke suggests an IHI imbalance may also relate to motor outcomes (Kirton et al. 2010). Developmental plasticity models of hemiparetic cerebral palsy following perinatal stroke are also emerging. While different from adult stroke, motor function also appears strongly associated with the relative balance of motor control between the two motor cortices (Eyre 2007; Kirton 2013; Staudt 2007). Based on these models, recent randomized trials have shown that contralesional, inhibitory repetitive TMS can improve motor function in hemiparetic children with perinatal stroke (Gillick et al. 2014; Kirton et al. 2016). Transcallosal inhibition may therefore be a target for neuromodulation therapies of cerebral palsy and other motor disorders of the developing brain.

Despite this clinical relevance, interhemispheric motor control systems have not been well studied in disorders of the developing brain, limited in part by an incomplete understanding of the normal developmental neurophysiology of transcallosal inhibition. We aimed to describe the fundamental characteristics and functional correlates of bidirectional iSP and IHI in typically developing school-age children and adolescents. We hypothesized that transcallosal inhibition measured as iSP and IHI increase in strength during childhood and adolescence.

MATERIAL AND METHODS

Ethical Approval

Participants and guardians provided written consent/assent. Protocols were approved by the University of Calgary Research Ethics Board and conformed to standards set by the Declaration of Helsinki.

Participants

Healthy right-handed children and adolescents were recruited through our population-based Healthy Infants and Children Clinical Research Program. Parents reported children as healthy with typical neurodevelopment and the absence of any neuropsychiatric disorders or medications. Handedness was self-assessed at enrollment and scored using the Edinburgh Handedness Inventory. Participants were screened for published TMS safety criteria (Keel et al. 2001).

TMS Procedure

EMG.

Surface EMG was recorded bilaterally using Ag/AgCl electrodes (Kendall, Covidien) placed over the belly of the first dorsal interosseous (FDI) muscles. Reference electrodes were centered on the knuckle of the second phalange. EMG signals were amplified (×1,000; 2024F isolated amplifier, Intronix Technologies), band-pass filtered (20–2,000 Hz), and recorded (CED1401 signal analog/digital converter; Cambridge Electronic Design). Muscle activation and strength were displayed in real time using a digital oscilloscope (GDS-1022, GW Instek). FDI activation was performed by squeezing a stress ball with the proximal regions of the thumb and index finger (flexion).

TMS.

TMS was performed using standard methodologies (Kobayashi and Pascual-Leone 2003). Single-pulse TMS was first applied over the approximated region of M1 using a 70-mm figure-of-eight coil attached to the Magstim 2002 magnetic stimulator (Magstim). The coil was placed tangential to the scalp, angled 45 degrees to midline. Stimulation was initially applied at 30% stimulator output and increased until visible FDI contractions were seen. Grid-mapping determined the optimal coil location for maximal FDI MEP. This “hotspot” was marked on a generic brain MRI template using neuronavigation (Brainsight, Rogue Research), allowing for accurate, consistent stimulation. Stimulator output was slowly reduced to determine the resting motor threshold (RMT), defined as the stimulator output required to produce five 50 μV MEP in 10 consecutive stimulations. RMT was determined for both the left and right M1.

Two TMS procedures investigated transcallosal inhibition (Fig. 1). First, we evaluated iSP from bilateral FDI (Fig. 1A). Participants were required to contract the FDI ipsilateral to the stimulation at 50% of their maximum voluntary contraction (based on response when participants maximally flexed their FDI by squeezing a stress ball) with this target displayed on the oscilloscope. Suprathreshold single pulse TMS was delivered to M1 at 120% of the stimulated hemisphere’s RMT. Ten stimuli, each separated by 5 s, were performed for each hand. Only the first five responses from each hand were included in the final analysis, as retroactive analysis suggested that iSP latency, duration, and suppression from the first-three and last-three stimuli differed in the left nondominant hand. These changes were likely caused a decrease in contraction strength, related to muscle fatigue (left hemisphere-iSP contraction strength EMG of first-three vs. last-three trials, 0.296 vs. 0.250 mV, P = 0.024; right hemisphere-iSP contraction strength EMG of first-three vs. last-three trials, 0.248 vs. 0.243 mV, P = 0.718). To ensure consistency across participants, iSP was tested from the left hemisphere first, and right hemisphere next, always separated by a minimum of 20 min. Second, we evaluated IHI in both the left-to-right and right-to-left M1 directions with both FDI at rest (Fig. 1C). Two Magstim 2002 magnetic stimulators were paired to perform paired-pulse TMS. One 70-mm figure-of-eight coil was placed over each M1 hotspot simultaneously. Left-to-right paired-pulse TMS was always performed first, where a 120% RMT conditioning stimulus was applied to the left M1, followed by a 120% RMT test stimulus to the right M1. The two stimuli were separated by randomly ordered [randomized in real-time through Signal 6.0 software (Cambridge Electronic Design)] interstimulus intervals (ISI) of 8, 10, 40, or 50 ms. A total of 50 stimuli were applied in each direction (10 per ISI, with 10 test stimuli alone). The same procedure was repeated in the right-to-left direction. At least 5 min separated iSP from IHI measures.

Fig. 1.

Fig. 1.

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Transcranial magnetic stimulation (TMS) paradigms. A: ipsilateral silent period (iSP) paradigm. A figure-of-eight TMS coil is centered over the first dorsal interosseous (FDI) motor hotspot and stimulation is delivered while the ipsilateral FDI is contracted. Example given depicts right hemisphere evoked iSP. B: rectified electromyography (EMG) of an iSP trace. Background EMG is averaged from prestimulus artifact EMG. Latency refers to the time from the stimulus artifact to the start of the iSP. Duration of the iSP refers to the time from the iSP start to end. Suppression strength of the iSP refers to the average amount of suppression from 25% background EMG. C: paired-pulse interhemispheric inhibition (IHI) paradigm. A figure-of-eight TMS coil is centered over each FDI motor hotspot. Two stimuli, a conditioning stimulus followed by a test stimulus, are applied with an interstimulus interval (ISI) of 8, 10, 40, or 50 ms. Both FDI remain at rest. Example given shows right-to-left IHI. D: EMG of an IHI tract. The amplitude of a conditioned motor evoked potential (MEP) (40-ms ISI; gray) is compared with that of an unconditioned test stimulus (test stimulus alone; black).

EMG Analysis

The EMG was rectified offline for analysis of iSP characteristics (Fig. 1B). First, 200 ms of background EMG before stimulation was averaged to determine the amplitude of background EMG. The start of the silent period was manually delineated as the time point at which EMG amplitude dropped below 25% of background EMG amplitude; the end of the silent period was defined as the time point at which EMG amplitude returned above 25% of background. Silent period duration was the time between the start and end of the silent period. Suppression strength was defined as the average amount by which the EMG amplitude dropped below the 25% background EMG threshold within the selected silent period. The area of iSP was calculated as the product of suppression strength and iSP duration. Silent period latency was the difference in time from the stimulus artifact to start of the silent period. Frames were excluded from final analysis if no iSP was present; based on published data an iSP was considered present if it occurred between 25 and 60 ms after the stimulus artifact and had a duration of at least 2.5 ms (Chiappa et al. 1995; Meyer et al. 1995; Wassermann et al. 1991). Measures were performed using an in-house designed MATLAB script. The EMG for IHI measures was analyzed offline (Fig. 1D). Test stimuli MEP amplitudes were averaged. IHI was expressed as a ratio of the conditioned MEP amplitude over the test stimuli MEP amplitude. Frames were excluded if the conditioning stimulus failed to evoke an MEP in the contralateral hand.

Purdue Pegboard Test

The Purdue Pegboard Test (PPT) was performed bilaterally to assess unimanual hand performance (Tiffin and Asher 1948). The PPT is a simple task where participants have 30 s to place pegs into a pegboard using either their left (PPTL) or right hand (PPTR). The total number of pegs placed is scored, and the average score of three repetitions per hand is calculated.

TMS Tolerability

Immediately following TMS, participants completed a modified pediatric brain stimulation safety and tolerability questionnaire (Garvey et al. 2001). The presence and severity of symptoms (headaches, neck pain, unpleasant tingling, nausea, and light-headedness) were self-reported. Participants ranked the tolerability of their TMS session compared with seven common childhood experiences.

Statistical Analysis

Statistical analysis was performed using SigmaPlot 12.5 (Systat Software). When applicable, results are expressed as mean values ± standard deviation. Left and right hemisphere outcomes, including RMT, iSP duration, iSP latency, iSP suppression strength, iSP area, and IHI, were compared using a paired-samples t-test. Correlations between continuous linear variables, such as RMT, iSP characteristics, IHI, and age were measured using Pearson’s correlation. One-sample t-test determined whether a given ISI resulted in IHI (compared with a ratio of 1.0, suggesting no difference in MEP amplitude from that of the test stimulus alone). Correlations between ranked variables, including number of stimuli failing to evoke an iSP and TMS tolerability, with age, were measured using Spearman’s correlation. PPTL scores were compared with PPTR scores using a paired-samples t-test. Because age influences PPT performance (Mathiowetz et al. 1986; Wilson et al. 1982), multiple linear regression was used to determine whether age and iSP components could predict PPT score.

RESULTS

Demographics

Twenty-four healthy children and adolescents meeting inclusion criteria were recruited. Five were excluded from the final analysis to maintain complete bilateral neurophysiological data sets (described below). The 19 participants included in the final analysis had a mean age of 14.5 ± 2.9 yr (range: 10.4–18.3 yr), a sex distribution of 9 boys:10 girls, and a mean laterality index of 80.6 ± 14.1 (range: 60.0–100).

RMT

The RMT was too high to measure in several young participants including being unobtainable from both hemispheres in one (7.4 yr), from the left hemisphere in two (9.0, 13.3 yr) and from the right hemisphere in two (8.9, 11.6 yr). Mean RMT was lower in the left hemisphere compared with the right (Fig. 2A; 43.7 ± 9.8 vs. 47.1 ± 10.9% maximum stimulator output; t = −2.56, P = 0.020). Left hemisphere RMT was inversely correlated with age (Fig. 2E; r = −0.430, P = 0.075) with an even stronger correlation observed in the right hemisphere (r = −0.551, P = 0.018).

Fig. 2.

Fig. 2.

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Transcranial magnetic stimulation (TMS) neurophysiology outcomes of the left (gray bars and circles) and right (white bars and black circles) primary motor cortex (M1). A: resting motor threshold (RMT). B: ipsilateral silent period (iSP) duration. C: iSP latency. D: iSP suppression strength. Data show group mean (± standard error). E: correlation of hemispheric RMT with age. F: correlation of hemispheric RMT and laterality according to the Edinburgh Handedness Inventory. G: correlation of iSP latency evoked from the left or right hemisphere (LH- or RH-iSP) with age. H: correlation of iSP suppression strength evoked from the left or right hemisphere (LH- or RH-iSP) with age. *P < 0.05.

iSP Characteristics

iSP was evoked bilaterally in all participants. No differences were seen in the number of successful iSP evoked in each hemisphere; 72 of 95 (76%) total stimuli applied to the left hemisphere (LH-iSP) and 79% in the right hemisphere (RH-iSP). Rank order correlation demonstrated a strong relationship between the likelihood of producing an iSP from the left hemisphere and age, where older participants were more likely to have iSP (ρ = 0.627, P = 0.005). This strong correlation with age was not seen in the right hemisphere (ρ = 0.356, P = 0.143).

The duration of the iSP did not differ between hemispheres (Fig. 2B). In left hemisphere stimulation, the duration of the LH-iSP was 15.6 ± 6.2 ms, compared with 14.1 ± 4.5 ms from the right (t = 1.18, P = 0.256). iSP duration was not correlated with age in either hemisphere (LH-iSP, r = 0.115, P = 0.646; RH-iSP, r = 0.015, P = 0.963) and did not differ between boys and girls (P > 0.276 in both hemispheres).

Latency of the iSP differed between stimulation of the left or right hemisphere (Fig. 2C). The latency of LH-iSP (40.9 ± 6.1 ms) was longer from that of RH-iSP (37.5 ± 3.9 ms; t = 2.15, P = 0.046). Latency of the LH-iSP (Fig. 2G; r = −0.411, P = 0.090) and RH-iSP (r = −0.631, P = 0.005) were negatively correlated with age. Latency of the RH-iSP appeared longer in girls compared with boys (39.8 ± 3.0 vs. 34.6 ± 2.8 ms; t = 3.775, P = 0.002). Similarly, latency of the LH-iSP was longer in girls compared with boys, approaching significance (43.1 ± 6.3 vs. 38.1 ± 4.6 ms; t = 1.875, P = 0.079). There was no difference in age between boys and girls.

There was a significance difference in suppression strength between LH-iSP and RH-iSP (Fig. 2D). Suppression strength of LH-iSP was stronger compared with RH-iSP (Fig. 2G; 0.117 ± 0.058 vs. 0.091 ± 0.036 mV; t = 2.156, P = 0.030). Suppression strength was correlated with age in RH-iSP (r = 0.488, P = 0.040), where older children displayed stronger suppression strength. The strength of suppression did not differ between boys and girls (P > 0.540 in both hemispheres).

There was a significant difference in iSP area between LH-iSP and RH-iSP. Area of LH-iSP was larger compared with RH-iSP (1.791 ± 1.108 vs. 1.229 ± 0.533 mV*ms; t = 2.823, P = 0.012). Area of iSP was not correlated with age in either hemisphere (LH-iSP, r = 0.372, P = 0.129; RH-iSP, r = 0.369, P = 0.131). The area of ISP did not differ between boys and girls in either hemisphere (both P > 0.185).

Secondary analysis using all trials, rather than the reduced number intended to accommodate participant fatigue (as described in TMS under TMS Procedure above), demonstrated similar trends in iSP duration, latency, and suppression strength. For either hand, we did not observe correlations between maximum voluntary contraction and age or sex or laterality index.

IHI

Eight participants displayed left-to-right IHI (conditioned MEP amplitude ratio <1.0) at all ISI tested, with the remaining lacking IHI for at least one ISI. In contrast, 13 participants showed right-to-left IHI with all ISI tested. On average, all ISI in both the left-to-right and right-to-left direction produced IHI (Fig. 3A; all P < 0.002). There was no difference in conditioned MEP amplitude ratios across different ISI within a direction, or within an ISI between directions, although mean MEP amplitudes were consistently lower in the right-to-left direction. When all ISI were combined, MEP amplitudes were more inhibited in the right-to-left than left to right-direction (0.785 ± 0.260 MEP ratio vs. 0.684 ± 0.266 MEP ratio; t = 2.485, P = 0.015). This greater right-to-left than left-to-right inhibition was more pronounced in girls (0.647 ± 0.234 MEP ratio vs. 0.756 ± 0.209 MEP ratio; t = 2.186, P = 0.036) than boys (0.720 ± 0.294 MEP ratio vs. 0.814 ± 0.303 MEP ratio; t = 1.437, P = 0.160); however, no differences were seen between girls and boys (left-to-right IHI, t = −0.524, P = 0.602; right-to-left IHI, t = −0.626, P = 0.535). Age was not correlated with IHI in either direction (all P > 0.250).

Fig. 3.

Fig. 3.

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Paired-pulse interhemispheric inhibition (IHI) measures. A: bidirectional IHI measured when the conditioning stimulus was applied to the left hemisphere and the test stimulus to the right hemisphere (left-to-right IHI; gray bars), and the conditioning stimulus applied to the right hemisphere and the test stimulus to the left hemisphere (right-to-left IHI; white bars). The amplitude of the conditioned MEP is compared with that of an unconditioned test stimulus (1-mV test stimulus). Stimuli are separated by various interstimulus intervals (ISI). Data show group mean (± standard error). B: correlation of left-to-right IHI at 8 (gray circles) or 10 ms (black circles) ISI and laterality according to the Edinburgh Handedness Inventory. C: correlation of right-to-left 8 (gray circles) or 10 ms (black circles) ISI and laterality. *P < 0.05.

Amplitude of the test stimulus MEP was correlated with age in the left-to-right IHI direction (r = 0.569, P = 0.014), but not the right-to-left direction (r = 0.379, P = 0.121). Because paired-pulse inhibition may be related to the size of test MEP, a multiple linear regression tested whether age and test stimulus MEP amplitude predicted the IHI MEP ratio. In both directions, at all ISI, neither age nor test stimulus MEP amplitude were significant for predicting IHI MEP ratio (all P > 0.537).

Handedness was positively correlated with bidirectional IHI at 8- and 10-ms ISI, such that more lateralized participants had less inhibition in both directions (Fig. 3, B and C). The correlation was strong in the left-to-right direction at both the 8- (r = 0.548, P = 0.015) and 10-ms ISI (r = 0.540, P = 0.017). In the right-to-left direction there was a significant correlation at the 8-ms ISI (r = 0.476, P = 0.046), with a possible trend observed at the 10-ms ISI (r = 0.409, P = 0.092). There was no correlation with handedness at the longer 40- and 50-ms ISI.

iSP IHI Correlation

Previous reports in adults have demonstrated correlations between iSP suppression strength and IHI (Chen et al. 2003). As such, we investigated the relationship between iSP suppression strength and IHI in children. Left-to-right IHI at 50-ms ISI was trending toward a negative correlation with LH-iSP suppression strength (Fig. 4; r = −0.423, P = 0.080), where those with stronger iSP suppression had smaller MEP amplitude ratios. At all other ISI, there was a consistent but not statistically significant negative association between left-to-right IHI and LH-iSP (8 ms, r = −0.075, P = 0.768; 10 ms, r = −0.154, P = 0.541; 40 ms, r = −0.279, P = 0.262). Right-to-left IHI at 40-ms ISI was positively correlated with RH-iSP suppression strength (Fig. 4; r = 0.641, P = 0.004), such that those with stronger iSP suppression had less IHI (larger MEP amplitude ratio). At all other ISI there was a weaker positive correlation between right-to-left IHI and RH-iSP (8 ms, r = 0.212, P = 0.398; 10 ms, r = 0.347, P = 0.158; 50 ms, r = 0.154, P = 0.542).

Fig. 4.

Fig. 4.

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Correlation of ipsilateral silent period (iSP) suppression strength with paired-pulse interhemispheric inhibition (IHI). Gray circles display correlations between iSP suppression strength evoked from the left hemisphere (LH-iSP) with IHI measured when the conditioned stimulus was applied to the left hemisphere and the test stimulus to the right hemisphere (left-to-right IHI) separated by a 50-ms ISI. Black circles demonstrate correlations between iSP suppression strength evoked from the right hemisphere (RH-iSP) with IHI measured when the conditioned stimulus was applied to the left hemisphere and the test stimulus to the right hemisphere (right-to-left IHI) separated by a 50-ms ISI.

Hand Function Correlations

Participants scored higher on the PPTR than the PPTL (16.1 ± 1.7 vs. 14.5 ± 1.4; t = 8.139, P < 0.001). PPTL scores showed a significant relationship with RH-iSP suppression duration and strength, where shorter iSP of stronger suppression from the right M1 was correlated with higher left hand scores (Fig. 5). Likewise, a similar relationship was seen between PPTR scores and LH-iSP suppression duration and strength. In both models, age (PPTR, t = 3.191, P = 0.007; PPTL, t = 3.090, P = 0.008) and iSP duration (PPTR, t = −2.950, P = 0.011; PPTL, t = −2.726, P = 0.016) were able to predict PPT score. In the multiple linear regression suppression duration did not appear to predict PPT score.

Fig. 5.

Fig. 5.

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Correlation of ipsilateral silent period (iSP) duration with Purdue Pegboard Test (PPT) scores. Gray circles display correlations between iSP duration evoked from the right hemisphere (RH-iSP) with left hand PPT scores (PPTL). Black circles demonstrate correlations between iSP duration evoked from the left hemisphere (LH-iSP) with right hand PPT scores (PPTL).

TMS Tolerability

All TMS procedures were well tolerated. Two participants reported mild neck pain following TMS and one participant reported mild tingling. Sensations were temporary and ended shortly after the stimulation. Self-reported tolerability scores of TMS were 3.89 ± 1.13, comparable to watching TV (2.97 ± 1.78) or a long car ride (4.73 ± 1.22). Tolerability scores were not correlated with age (ρ = 0.188, P = 0.451).

DISCUSSION

Here we used two TMS paradigms to assess transcallosal motor inhibition in typically developing children and adolescents. Components of the iSP appear to mature throughout development, may not be symmetric between hemispheres and differ between boys and girls. We demonstrated that IHI is present by school age in typically developing children and adolescents, revealing directional and sex-specific differences in inhibition patterns and associations with handedness. Direct comparison identified overlapping but also distinct features between IHI and iSP measures of interhemispheric inhibition. Finally, we identified iSP components associated with motor performance, further supporting clinical relevance and a potential neurophysiological target for neuromodulation.

Ipsilateral Silent Periods

The developmental profile of iSP has been previously investigated in children (Garvey et al. 2003); however, our study brings additional methodological differences. The study of Garvey et al. (2003) stimulated M1 in all age groups (from children to young adults) at 100% stimulator output. Younger children had longer iSP durations compared with older children and adults; however, this may have been in part due to such high, standardized stimulus intensities. In contrast, our suprathreshold stimulations were proportional to each individual’s RMT and may therefore have been more applicable for comparison across age groups. Ipsilateral inhibition studies suggest that iSP duration increases with stimulator output in adults (Meyer et al. 1995). Adults are regarded as having a more stable RMT, as the largest changes in RMT take place throughout early development; therefore the “effective dose” of a given stimulator output may be more predictable, where an increase in stimulator output by x% increases a response by x-amount, with relatively little variability in adults. In developing children, the RMT is age dependent, as demonstrated by our findings and others (Eyre et al. 1991). Standardizing the effective dose of stimulation to 120% RMT may be favorable to a consistent % stimulator output; the effective dose of 100% stimulator output stimulation in a child with an RMT of 70% stimulator output differs from that of a child with an RMT of 30% stimulator output, such that those with a lower RMT receive a larger dose; therefore changes in iSP duration may not be solely due to age, but rather to effective dose of stimulation, or a combination of both. Indeed, when a standardized dose of stimulation was given at 120% of each child’s RMT, we no longer observed a correlation of iSP duration with age. Replicating earlier findings, we found that in children over 10 yr of age there is no difference in the duration of iSP evoked from the left or right hemisphere and that iSP latency showed hemispheric differences. The finding of differences in iSP latency may be related to increased myelination of white matter tracts that proceeds throughout development (Paus et al. 1999), facilitating iSP.

Further discrepancies arise between our findings and that of Garvey et al. (2003). We found that suppression latency and strength were the only components of the iSP that showed differences between hemispheres, where the left hemisphere evokes stronger transcallosal inhibition of longer latency than the right hemisphere. As these were right-handed children, this corresponds to the dominant hemisphere exerting more pronounced delayed inhibition than the nondominant hemisphere. This is in accordance to findings in right-handed adults (Reid and Serrien 2012). Other components of the iSP, including duration, appear to display hemispheric symmetry between left- and right-handed adults (Davidson and Tremblay 2013). As children mature, we found that suppression strength evoked from either hemisphere increases, with suppression latency decreasing. Studies applying diffusion tensor imaging have revealed changes in the integrity of white matter tracts throughout development. Whereas certain projecting tracts such as upper corticospinal tracts are mature by adolescence, the corpus callosum, which facilitates transcallosal interactions, remains immature in adolescence (Asato et al. 2010; Yap et al. 2013); our correlations of iSP latency and suppression strength support this developmental notion, as latency continued to decrease with age, and suppression strength increased. Furthermore, this increased suppression may progress and strengthen as children develop increased unimanual and bimanual abilities, which may require more precise coordination of motor control between hemispheres. Alternately, this may reflect myelination of the callosal fibers, increasing synchrony of volleys across the corpus callosum, possibly allowing for greater recruitment of contralateral circuits.

Interhemispheric Inhibition

We demonstrated that IHI can be consistently demonstrated in healthy children and adolescents using bilateral M1, paired-pulse TMS. As with previous reports in adults, when stimuli are separated by an ISI of 8–50 ms, inhibition of MEP is observed (Chen et al. 2003; Ferbert et al. 1992; Gerloff et al. 1998). We demonstrate that inhibition was stronger when the right, nondominant, hemisphere was conditioned. Lack of inhibition (MEP amplitude ratio ≥1.0) was more common in the left-to-right direction, where nine children did not consistently demonstrate IHI across all ISI. This lack of inhibition in children may suggest ongoing development of the corpus callosum, which is thought to mediate transcallosal facilitation (Hanajima et al. 2001). Transcallosal facilitation has been previously reported in adults; however, it is typically seen with shorter ISI of 2–5 ms (Chen et al. 2003; Hanajima et al. 2002). When all ISI were combined, inhibition was stronger in the right-to-left than left-to-right direction. Relative directional strength of transcallosal inhibition appears to be dependent on handedness in adults; however, the directional preference differs from that of children. In typically developing right-handed adults, conditioning the dominant hemisphere results in stronger IHI than when the nondominant hemisphere is conditioned (Bäumer et al. 2007; Netz et al. 1995) left-handed adults show no directional preference for IHI. These findings suggest that even in teenagers’ maturation of transcallosal pathways is ongoing, and the directional strength of IHI may reverse by adulthood.

Influence of Sex

Sex also appears to influence differences in directional strength of IHI, as well as iSP latency. Girls may display a greater asymmetry of right-to-left than left-to-right IHI, whereas boys displayed directional symmetry. Likewise, girls displayed iSP of significantly shorter latency than boys. Boys and girls have unique neurodevelopmental profiles. The corpus callosum thickens throughout development; however, in girls this may occur at a faster rate compared with boys (Giedd et al. 1997; Luders et al. 2010). The necessary role of the corpus callosum in IHI and iSP suggests that callosal thickness may influence the strength of transcallosal inhibition, and earlier maturation of white matter integrity in girls may facilitate shortened iSP latency. Whether the unique IHI and iSP profiles of male and female children is solely due to differences in callosal thickness remains to be investigated. Advances in diffusion tensor imaging can identify properties of transcallosal fibers (such as anisotropy and diffusivity) that may differ between boys and girls, complementing our neurophysiological findings. Although typically referred to as a single phenomenon, IHI is progressively understood as having distinct components. IHI is increasingly divided into short (8- to 10-ms ISI) and long (40- to 50-ms ISI) forms that have distinct properties (Chen et al. 2003; Kukaswadia et al. 2005). For example, in adults, muscle activation reduces the short, but not long, components of IHI (Chen et al. 2003). Although there was no difference in the strength of short and long IHI in either direction, each component did correlate with unique factors in healthy children. For example, we found that short IHI correlated with handedness, where more lateralized individuals showed weaker IHI in both directions. These correlations were evident with both 8- and 10-ms ISI, suggesting overlapping phases. Long components of IHI however showed no correlation with handedness but instead were correlated with iSP suppression strength, further supporting distinct neurophysiological properties.

Relationship Between Ipsilateral Silent Periods and Interhemispheric Inhibition

Despite both representing transcallosal inhibition and having overlapping characteristics, iSP and IHI may be mediated by different mechanisms. A primary difference between iSP and IHI is that iSP represents a disruption of voluntary motor activity, whereas IHI requires a synchronization of two suprathreshold stimuli at rest. The responses of iSP and IHI do have certain similarities. For example, the optimal scalp location for iSP and IHI is the same, as is the linear relationship with strength up to ~75% of stimulator output (Chen et al. 2003; Ferbert et al. 1992; Wassermann et al. 1991). Long components of IHI show correlations with iSP suppression in healthy adults, where stronger IHI is correlated with stronger iSP; however, this was only examined in the right-to-left direction (Chen et al. 2003). Our findings are consistent with this study as we found that long phase IHI (50-ms ISI) in the right-to-left direction was positively correlated with iSP suppression strength of the left hemisphere in healthy children. Interestingly, in the left-to-right direction with 40-ms ISI, a negative correlation was seen with RH-iSP suppression strength. This negative correlation suggests that weaker suppression of the iSP is correlated with weaker IHI (or interhemispheric facilitation). This finding supports the idea that IHI and iSP may be mediated by the same neuronal circuitry, although this is primarily evident with long ISI. The lack of an overlap between short-phase IHI and iSP should not be ruled out as weaker correlations were seen with 8- and 10-ms ISI and iSP suppression strength, although the direction of correlation remained consistent (i.e., negative correlation in the left-to-right direction, and positive in the right-to-left direction). Our findings present seemingly inconsistent trends, where iSP findings suggest that the dominant hemisphere exhibits stronger transcallosal inhibition than the nondominant hemisphere; however, according to our IHI findings the nondominant hemisphere generates stronger inhibition. These contradictory findings may be explained by the fact that iSP requires background activation of the contralateral hemisphere, whereas IHI is performed at rest, and therefore the state of the central nervous system may not be comparable between these two paradigms. As suggested by others (Chen et al. 2003), iSP and IHI should probably best be regarded as complementary, rather than equivalent, assessments of transcallosal inhibition.

Relationship Between Ipsilateral Silent Periods and Motor Function

We found significant relationships between suppression duration and unimanual hand performance scores. Suppression duration of the left (dominant) hemisphere showed a relationship with the contralateral right hand PPT scores, and right (nondominant) hemisphere suppression duration with left hand PPT scores. These findings suggest that decreased ipsilateral suppression from the contralateral hemisphere may be associated with higher unimanual motor function. Measurements of the corpus callosum suggest that in right-handed children a thicker corpus callosum is correlated with higher PPT scores (Kurth et al. 2013). This thickening may be representative of increased axonal density, thicker axons, or greater myelination, possibly facilitating a higher degree of interhemispheric connectivity. These anatomical callosal studies appear consistent with our findings that stronger transcallosal inhibition of the contralateral hemisphere is associated with improved motor function.

Noninvasive brain stimulation technologies such as transcranial direct-current stimulation enhance motor learning in adults (Reis et al. 2009) and children (Ciechanski and Kirton 2016). Emerging evidence suggests that motor learning paired with transcranial direct-current stimulation changes the strength of transcallosal inhibition in adults (Williams et al. 2010). Interestingly, greater motor improvements were correlated with larger shifts in transcallosal inhibition. It is hoped that the improved understanding of the developmental properties of transcallosal inhibition described here will facilitate model development and the creation and evaluation of neuromodulatory therapies for children with motor disabilities.

GRANTS

Experiments were performed at the Alberta Children’s Hospital Noninvasive Brain Stimulation Laboratory in Calgary, Canada. Funding for this study was provided by Alberta Innovates Health Solutions, Heart and Stroke Foundation of Canada and the Alberta Children’s Hospital Foundation. Funding for P. Ciechanski was provided by Alberta Innovates Health Solutions and the Canadian Institutes of Health Research.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

P.C. and A.K. conceived and designed research; P.C. performed experiments; P.C. and E.Z. analyzed data; P.C., E.Z., and A.K. interpreted results of experiments; P.C. prepared figures; P.C. drafted manuscript; P.C., E.Z., and A.K. edited and revised manuscript; P.C., E.Z., and A.K. approved final version of manuscript.

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