Repetitive transcranial magnetic stimulation influences cognitive-motor dual-task performance in children with cerebral palsy: a randomized controlled study

Abstract

Background

Children with cerebral palsy (CP) may face challenges when engaging in activities that require simultaneous cognitive and motor efforts. Repetitive transcranial magnetic stimulation (rTMS) has the potential to improve motor and cognitive functions in some populations. However, the effect of rTMS on the performance of cognitive-motor dual-task in children with CP remains unclear.

Objective

To investigate the efficacy and safety of rTMS on the performance of cognitive-motor dual-task in children with CP.

Methods

In this randomized controlled trial, forty-four children with CP (aged 6–12 years) were recruited. They were randomly allocated to receive 3 consecutive sessions of active or sham rTMS applied to the left dorsolateral prefrontal cortex (DLPFC). Participants were asked to perform the Box and Block Test (BBT) and Serial Subtraction Test (SST) separately or simultaneously before and immediately after each rTMS session.

Results

Forty participants completed the study (22 in the active rTMS group). On day 3, significant enhancements were observed in SST scores for the active rTMS group compared to the sham group (single-task:14.4 ± 1.6 vs. 8.89 ± 1.8, p = 0.024; dual-task: 9.36 ± 1.0 vs. 3.89 ± 1.1, p = 0.001). Under the dual-task condition, the active rTMS group displayed a greater improvement in BBT scores than the sham group on day 3 (8.91 ± 1.03 vs. 3.83 ± 1.14, corrected p = 0.003). There were no notable differences between the two groups in the improvement of BBT scores under the single-task condition. No serious adverse events were reported.

Conclusion

The rTMS applied to the left DLPFC is safe and effective in improving the performance of cognitive-motor dual-task in children with CP.

Introduction

Cerebral palsy (CP) is the leading cause of lifelong physical disability, affecting approximately 2.3–3.4 per 1000 live births worldwide [1]. Approximately 60% of children with CP suffer from varying degrees of upper limb impairments [2]. These impairments, characterized by spasticity, limited range of motion, and deficits in motor control, may negatively affect their ability to perform upper limb activities such as reaching, grasping, and releasing. Furthermore, among all children with CP, intellectual disabilities are prevalent in approximately 50% of cases, with attention, executive functions, and visual-spatial abilities being the domains most commonly impacted [3, 4]. These motor and cognitive impairments may pose significant challenges for children with CP, even those with subtle deficits, in effectively performing dual-tasks that require cognitive engagement.

In fact, cognitive and motor skills are imperative for successful engagement in daily activities. Many daily activities require performing cognitive and motor tasks simultaneously, such as walking while talking or taking notes while listening to a lecture. Studies have shown that children with CP exhibit greater dual-task interference (worse performance in one or both tasks under dual-task conditions compared with single-task conditions) while performing dual-tasks compared to typically developing peers [5–7]. For example, engaging in dual-tasks can negatively impact walking performance and interfere with postural control [7, 8]. These may further impair the individuals’ ability to participate in educational activities, social interactions, and basic self-care routines. Moreover, studies have indicated that children with hemiplegic CP (HCP) have greater activation in the prefrontal cortex (PFC) while performing dual-tasks with their more affected upper hand compared to typically developing peers [6, 9]. As opposed to motor cortex, the activation in the PFC was not laterality specific since there was no differential activation within the right and left PFC while performing dual-tasks with their more affected hand [6]. This suggests that the children with CP may utilize greater cognitive and attentional resources to perform dual-tasks. Therefore, individuals with neural inefficiency need to recruit more cognitive resources for dual-tasks but still have poor dual-task performance, and neural transmission efficiency could be an more efficient strategy for better dual-task performance [10, 11]. Individuals are frequently challenged by dual-task conditions in daily life, hence, flexible adaptation to the changing motor and cognitive requirements of daily functions is necessary for successfully and independently performing activities of daily life. Therefore, it is imperative to develop and target interventions to improve dual-task performance and enhance the independence of children with CP in daily life.

Several studies have shown that using non-invasive brain stimulation (NIBS) techniques to increase excitability of the left dorsolateral PFC (DLPFC) significantly improved performance on dual-task walking and standing as well as cognitive performance. The two most common therapeutic forms of NIBS include transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) [12]. Ljubisavljevic et al. administered a 1.5-mA anodal tDCS session to the left DLPFC for 20 min in 22 older adults, reporting a significant improvement in dual-task cognitive performance [13]. Goh et al. reported that a single rTMS session targeting the left DLPFC was effective in improving dual-task gait speed in individuals with left chronic stroke [14]. The left DLPFC plays an important role in attention, executive function, working memory [15]. There is considerable evidence that DLPFC subserves critical cognitive abilities even during early infancy and that improvement in these abilities is evident over roughly the next 10 years [16]. Accordingly, based on the above findings, we suppose that interventions designed to enhance functional activation of the left DLPFC may improve dual-task performance in children with CP.

rTMS has relatively good focality and can deliver repeated, rapidly changing magnetic fields through the scalp and skull to generate local electrical currents, thereby modulating cortical neuronal activity [17]. rTMS is not only painless and noninvasive, but also has good safety with transient and mild adverse event [18]. Low-frequency rTMS (≤ 1 Hz) can suppress cortical excitability, while high-frequency rTMS (>1 Hz) can increase cortical excitability [19].

Several randomized trials have examined the effect of rTMS on upper limb function in children with hemiplegic CP, with a particular focus on the cortical motor areas [16, 17]. These studies have demonstrated that inhibitory, contralesional rTMS could improve the affected hand function of children with CP [20, 21]. Additionally, recent meta-analyses conducted in clinical populations such as Alzheimer’s disease, mild cognitive impairment, schizophrenia, neuropsychiatric disorders demonstrating high-frequency rTMS administered to the left DLPFC significantly improved cognitive performance [22–24]. Nevertheless, the effect of rTMS on the performance of cognitive-motor dual-task in children with CP remains unclear. Therefore, the objective of this study was to investigate whether rTMS applied to the left DLPFC could improve the performance on cognitive and motor tasks under the dual-task condition for children with CP.

Methods

Experimental design and blinding

This study was a randomized, controlled trial registered in http://www.chictr.org.cn(Identifier: ChiCTR2300069700). It had received approval from the Ethics Committee of Guangzhou Women and Children’s Medical Center. Written informed consent was obtained from the legal guardians of each participant before enrollment. Additionally, children over 8 years of age were also required to provide their written consent. After baseline assessment, participants were stratified according to their age (6 to 10 years and 10 to 12 years) and then were randomly assigned to receive either active or sham rTMS in a 1:1 ratio by random number table. Participants were randomized to groups and received the same stimulation protocol for 3 consecutive days, with each stimulation implemented at approximately the same time daily. Moreover, participants were asked to complete a 10-minute assessment before and immediately after each rTMS session (Fig. 1). The stimulation and assessment at each time point were conducted individually by two professionally trained researchers. Participants, legal guardians, clinical assessors, and other study staff were blinded to rTMS assignment.

Fig. 1.

Three-day timeline of the study. Box and Block Test (BBT, participants transported blocks from one compartment to the other one by one with the non-dominant hand as quickly as possible for 60s). Serial Subtraction Test (SST, participants counted backward every 1 number or 3 numbers from a number randomly generated from a range of 90 to 100 as quickly as possible for 60s). Dual-Task (DT, participants performed both BBT and SST as quickly as possible for 60s). All tasks (every single-task and dual-task) were assessed before and immediately after each rTMS session

Participants

Participants were recruited from the rehabilitation department of Guangzhou Women and Children’s Medical Center from March 2023 to September 2023. Inclusion criteria were as follows: (1) children who were diagnosed as spastic CP; [25] (2) aged 6–12 years; (3) Manual Ability Classification System (MACS) levels I-II; (4) Gross Motor Function Classification System (GMFCS) levels I–II; (5) ability to understand and follow commands; (6) the legal guardian and children over 8 years of age signed written informed consent. Exclusion criteria were as follows: (1) co-occurrence of other diseases not associated with CP (such as encephalitis or intracerebral hemorrhage); (2) uncontrolled seizures; (3) upper limb surgery or botulinum toxin injection within 6 months; (4) presence of contraindications for TMS (such as having metal within the cranium or a cardiac pacemaker); (5) severely damaged left DLPFC as evaluated using MRI.

rTMS intervention

Participants sat comfortably in a chair during the rTMS. rTMS was administered with a Magneuro stimulator (Nanjing Vishee Medical Technology CO., Ltd, China) through a butterfly-shaped coil. For both groups, single-pulse TMS was delivered to detect the motor-evoked potential (MEP) by monitoring the dominant abductor pollicis brevis muscle activity with electromyography. Each participant’s resting motor threshold (RMT) is defined as the minimum stimulation intensity required to elicit MEPs greater than or equal to 50µV peak-to-peak in at least 5 out of 10 consecutive stimulations, with the target muscle in a relaxed state [26]. The RMT was expressed as a percentage of the maximum stimulator output. In cases where a participant’s RMT was absent, a default setting of 40% of the maximum stimulator output was used, in alignment with the rough mean RMT in existing studies of rTMS for different groups of people [27, 28]. Subsequently, participants received rTMS targeting the left DLPFC region according to the international 10–20 EEG system. The stimulation parameters were determined based on previous studies that reported improvements in cognitive and behavioral outcomes [29, 30]. Accordingly, we adopted the following parameters: 90% RMT stimulation intensity; 5 Hz frequency; 5s on and 15s off; 1200 pulses per session; total duration of 20 min. The TMS coil was held in standard position, parallel to the left DLPFC, with the handle of the coil pointed backward at 45° relative to the midline. Sham stimulation was applied with a sham coil delivered at the same site and with identical parameters to mimic the auditory and tactile sensations of the active stimulation, without actually delivering any stimulation to the cortex. Additionally, to ensure treatment compliance and maintain head comfort and stillness during rTMS treatment, we implemented the following methods [18, 31]: (1) Lighting and room temperature are adjusted to provide for maximum participants comfort. (2) Ensure the participant is in a comfortable position, and use cushions to support the neck or back when necessary; (3) Reassuring the participants that what they are feeling is normal and engaging the participants in conversation as a form of distraction may help to minimize discomfort; (4) Promoting an atmosphere that allows participants and parents to ask questions and to receive accurate information allays fears, builds trust, and increases the tolerability of treatment, thus improving outcomes; (5) During the session, participants could watch cartoons or videos if they can not maintain stillness according to the above four methods.

Task assessments

Task assessments were conducted in the following order to eliminate potential sequence effects: (1) a single motor task; (2) a single cognitive task; (3) a cognitive-motor dual-task. The motor task was performed using the Box and Block Test (BBT), which is commonly used to evaluate manual dexterity, including essential hand functions such as grasping, holding, transferring, and releasing [32]. It is well documented that the BBT is appropriate for repeated measures to track daily changes and map motor learning curves in children with CP. More importantly, the BBT is recognized for its high test-retest reliability (intraclass correlation coefficient = 0.98) and shows no ceiling effects [33, 34]. In the administration of BBT, the children sat on a suitable chair in front of two compartment boxes placed on a table, one of which containing 150 blocks. The children were instructed to grasp and transfer the square blocks as many as possible, one block at a time, from one compartment to the other with the non-dominant hand. The score is determined by the number of blocks correctly transported within 60s. A larger number of blocks indicates better manual dexterity ability.

The cognitive task was performed by the verbalized Serial Subtraction Test (SST). Participants started with a number that was randomly generated from a range of 90 to 100. Depending on their age, children were asked to count backward every 1 number (6 to 10 years) or 3 numbers (10 to 12 years) as quickly as possible within 60s. The SST was chosen because it could activate a distributed cortical network, including the left DLPFC [35]. Additionally, it is a widely used paradigm in dual-task assessments and is minimally influenced by learning [36]. The answers were recorded on paper by the assessor, and the number of correct calculations was counted (if one or three was subtracted from the previous number correctly, it was regarded as a correct calculation). A greater number of correct answers indicates better performance.

In the dual-task condition, the selected initial number was shown when the BBT started, then the children were instructed to perform both tasks simultaneously as quickly as possible within 60s. Participants were asked not to prioritize either of the two tasks. The dual-task cost, calculated as [(scores in single-task– scores in dual-task)/scores in single-task] × 100%, indicates dual-task interference, with negative values suggesting better performance under dual-task than single-task conditions [37]. All the above tasks were assessed in a separate, quiet room with only the assessor and the participant present. This setup ensured that the participant did not receive any form of guidance or feedback during the assessment of the tasks, allowing for an accurate assessment of the net effect of rTMS. In order to allow sufficient recovery time for participants and minimize the possible effects of fatigue from consecutive assessments, a 1-minute rest period was instituted between each assessment test. Any adverse events that occurred during and at the end of each rTMS session were recorded, including scalp discomfort, headache, nausea, pain at the stimulation site, hearing problems, or other discomforts.

Statistical analysis

The sample size was calculated using G*power 3.1 (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany). In this preliminary study, the sample size was determined based on the results of a preceding experiment (with each group included 5 participants), which showed an improvement in SST scores under the dual-task condition of 8.47 ± 6.42 (mean ± SD) for the active group compared to 3.76 ± 2.20 (mean ± SD) for the sham group. We assumed that active rTMS would produce an effect size of 0.98 compared with sham treatment, with a power of 0.80 and a 2-tailed alpha level of 0.05. Assuming a dropout rate of 20%, we enrolled 44 participants in total. The efficacy and safety analyses were conducted only on participants who had adhered strictly to the intervention schedule. Statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics mean (standard deviation), number, or median (interquartile range) were calculated for all variables. The Shapiro-Wilk test was used to examine if the data was normally distributed. To analyse differences in baseline demographic and clinical characteristics between groups, the independent sample t-test or Mann-Whitney U test was employed for continuous variables, while the chi-square test was used for categorical variables. The within-group paired t-tests were used to compare dual-task costs between BBT and SST in both groups at baseline. Changes in BBT and SST scores from baseline (T0) to post-stimulation assessments of each day (T1, T2, T3) were analysed using repeated measures analysis of covariance, as implemented under a linear mixed model, with group, day, and their interaction as fixed effects and the participants as the random effect to account for individual differences. We included the baseline scores as covariates to adjust for baseline differences between the two groups and more important, to reduce error variance. The group and day interaction term was tested first. If significant, we performed simple effect analyses of between-group differences at each day (uncorrected α = 0.05). If not significant, the group main effect was tested next. Bonferroni correction was applied at each day, with p values adjusted by multiplying the nominal p value by the number of tests (truncated at 1.0). The effect sizes for the differences in change values between groups were calculated using Cohen’s d formula, with values greater than 0.8 indicating a notable effect size [38]. Independent t-tests were conducted to compare the reduction of dual-task cost to both BBT and SST scores between the two groups. The significant level was set at p<0.05.

Results

Baseline demographic and clinical characteristics

During the enrollment period, 71 participants with CP were assessed for eligibility. Of these, 27 were ineligible or declined to participate. 44 participants were randomly assigned to receive rTMS, and finally 40 participants completed the study and were included in the analysis (Fig. 2). The baseline demographic and clinical characteristics of the two groups were shown in Table 1. Age, gender, CP subtypes, the side of the non-dominant hand, GMFCS level, MACS level, baseline BBT scores under the single-task condition, and the dual-task cost to both BBT and SST scores did not significantly differ between the two groups. Notable differences were observed in the baseline SST scores under the single-task condition and the baseline BBT and SST scores under the dual-task condition between the two groups. There were no significant differences between dual-task cost to BBT scores and SST scores in the active rTMS group (t = 1.55, p = 0.136) or the sham group (t=-0.252, p = 0.804).

Fig. 2.

CONSORT trial flow diagram

Table 1.

Baseline demographic and clinical characteristics

Variables	Active rTMS (n = 22)	Sham rTMS (n = 18)	t/χ2	P
Age, mean (SD), y	9.57 (2.1)	8.94 (1.9)	t = 0.952	0.347
Gender, male/female, No.	14/8	13/5	χ2 = 0.952	0.564
CP type, Diplegia/hemiplegia, No.	10/12	9/9	χ2 = 0.082	0.775
side of affected hand, left/right, No.	14/8	13/5	χ2 = 0.333	0.564
GMFCS level, I/II, No.	18/4	15/3	χ2 = 0.016	0.900
MACS level, I/II, No.	19/3	18/0	χ2 = 2.654	0.103
Single-task BBT, mean (SD)	33.64 (10.8)	37.50 (10.6)	t=-1.415	0.157
Single-task SST, mean (SD)	24.32 (10.8)	40.11 (22.6)	t=-2.273	0.023
Dual-task BBT, mean (SD)	20.32 (8.5)	27.44 (9.6)	t=-2.315	0.021
Dual-task SST, mean (SD)	17.73 (5.8)	25.39 (10.1)	t=--2.613	0.009
DTC-BBT, mean (SD), %	35.33 (25.6)	24.40 (22.4)	t = 1.419	0.164
DTC-SST, mean (SD), %	21.91 (21.4)	26.77 (27.0)	t=--0.636	0.529
Resting MEP, presence/absence, No.	17/5	15/3	-	-
RMT*, mean (SD), %	52.50 (6.3)	55.94 (7.8)	t = 1.423	0.169
MRI, No.
periventricular leukomalacia	11	11	-	-
ventricle broadening	6	3	-	-
malformation	3	2	-	-
normal	2	2	-	-

Notes. rTMS, repetitive transcranial magnetic stimulation; CP, cerebral palsy; GMFCS, Gross Motor Function Classification System; MACS, Manual Ability Classification System; BBT, Box and Block Test; SST, Serial Subtraction Test; DTC, Dual-task cost; MEP, motor evoked potential; RMT, resting motor threshold; MRI, magnetic resonance imaging

* Mean data from only those participants with available MEP as indicated

Notes. rTMS, repetitive transcranial magnetic stimulation; CP, cerebral palsy; GMFCS, Gross Motor Function Classification System; MACS, Manual Ability Classification System; BBT, Box and Block Test; SST, Serial Subtraction Test; DTC, Dual-task cost; MEP, motor evoked potential; RMT, resting motor threshold; MRI, magnetic resonance imaging. * Mean data from only those participants with available MEP as indicated

The effects of rTMS on dual-task performance

The change curves for both BBT and SST scores under the dual-task condition by the two groups were shown in Fig. 3 (A-B). The BBT and SST scores improved significantly after 3 sessions of rTMS compared to the baseline in both groups. For BBT scores, there was a significant main effect of group (F = 8.55, p < 0.01), but no significant interaction of group and day (F = 2.10, p = 0.131). Post hoc tests used Bonferroni correction showed differences on day 2 (F = 6.617, corrected p = 0.036) and day 3 (F = 11.451, corrected p = 0.003), but not on day 1 (F = 2.451, corrected p = 0.366). The effect size for this improvement of BBT scores in the active rTMS group was particularly notable, with Cohen’s d values of 0.92. For SST scores, there was a significant interaction between group and day (F = 4.23, p = 0.018). Simple effect analyses of between-group differences indicated that the active rTMS group displayed a significantly greater improvement in SST scores compared to the sham group on day 3 (p = 0.001) and day 2 (p = 0.004), but not on day 1 (p = 0.391). On days 2 and 3, the improvement in SST scores for the active rTMS group was more than double that of the sham group (day 2: 7.55 ± 1.0 vs. 3.00 ± 1.1; day 3: 9.36 ± 1.0 vs. 3.89 ± 1.1). The effect size for this improvement of SST scores in the active rTMS group on day 3 was particularly notable, with Cohen’s d values of 0.93. We also found that the dual-task cost to BBT scores achieved clinically significant reductions after 3 days of active rTMS intervention (p = 0.035), even though there was no significant between-group difference (p = 0.174) (Fig. 4A). For the dual-task cost to SST scores, there were no significant within-group or between-group differences (p = 0.759) (Fig. 4B).

Fig. 3.

The mean change curves of the Box and Block Test (BBT) and Serial Subtraction Test (SST) scores for both groups at all time points. Each time point represents the mean change of scores between the assessment after each rTMS session (T1, T2, T3) and baseline (T0). (A) Mean change curves of BBT scores under the dual-task condition. (B) Mean change curves of SST scores under the dual-task condition. (C) Mean change curves of BBT scores under the single-task condition. (D) Mean change curves of SST scores under the single-task condition. Error bars indicate standard errors of the mean. All p-values reflect Bonferroni corrections, truncated at 1.0, as appropriate (see text). *p < 0.05, **p < 0.01

Fig. 4.

The dual-task costs to both Box and Block Test (BBT) and Serial Subtraction Test (SST) scores for the two groups at baseline and day 3. Error bars indicate standard errors of the mean. *p < 0.05

The effects of rTMS on single-task performance

The change curves for both BBT and SST scores under the single-task condition by the two groups were shown in Fig. 3 (C-D). The BBT and SST scores improved significantly after 3 sessions of rTMS compared to the baseline in both groups. For BBT scores, there was no significant interaction between group and day (F = 2.27, p = 0.110) nor a significant main effect of group (F = 3.10, p = 0.086). Post hoc tests used Bonferroni correction showed no differences on day 1 (F = 0.492, corrected p = 1.00), day 2 (F = 1.118, corrected p = 0.882) and day 3 (F = 6.917, corrected p = 0.054). The effect size for this improvement of BBT scores in the active rTMS group on day 3 was notable, with Cohen’s d values of 0.86. In contrast, there was a significant interaction between group and day in SST scores (F = 3.28, p = 0.043). Post hoc analyses of this interaction indicated that the active rTMS group displayed a greater improvement in SST scores compared to the sham group on day 3 (p = 0.024), but not on day 1 (p = 0.823) and day 2 (p = 0.159). On day 3, the improvement in SST scores for the active rTMS group was more than 1.5 times that of the sham group (14.4 ± 1.6 vs. 8.89 ± 1.8). The effect size for this improvement of SST scores in the active rTMS group on day 3 was notable, with Cohen’s d values of 0.85.

Adverse events

Adverse events that occurred during and at the end of each rTMS session were monitored and recorded for 3 days. The overall number of reported adverse events was similar between the two groups (Table 2). In the active rTMS group, adverse events occurred in 4 participants, of which two children had headaches, and two experienced scalp discomfort. In the sham rTMS group, 2 children reported headache. These discomforts were mild, transient and self-resolved after stimulation. Importantly, no serious adverse events were reported in either group.

Table 2.

Number of participants reporting each adverse event (%)

Variables	Active rTMS (n = 22)	Sham rTMS (n = 18)
Scalp discomfort	2 (9.1%)	0 (0%)
Headache	2 (9.1%)	2 (11.1%)
Nausea	0 (0%)	0 (0%)
Pain at the stimulation site	0 (0%)	0 (0%)
Other discomforts	0 (0%)	0 (0%)
Total	4 (18.2%)	2 (11.1%)

Notes. rTMS, repetitive transcranial magnetic stimulation

Discussion

To the best of our knowledge, this randomized controlled trial is the first study to investigate the effect of rTMS applied to the left DLPFC on the performance of cognitive-motor dual-task in children with CP. It was found that the active rTMS group induced significantly faster and more pronounced improvements in SST scores compared to the sham group, in both single-task and dual-task conditions. Regarding BBT scores, the active rTMS group showed a significantly greater improvement under the dual-task condition than the sham group. Self-reported adverse events were similar between the two groups and no serious adverse events occurred during the intervention period.

Several studies demonstrated bilateral PFC and DLPFC activation while performing dual-tasks [11, 39, 40]. Surkar et al. reported that there are no hemispheric differences in the activation of the PFC while performing dual-tasks with the affected or the less affected hand in children with HCP [6]. In our study, we prioritized the left DLPFC as a stimulation target based on the following three reasons. First, the left DLPFC has been the target site of most research interest in enhancing cognition. The left DLPFC is a highly linked node in the central executive network that is associated with mood regulation and higher-level cognitive processes including working memory and cognitive flexibility [15, 41]. Second, several studies have shown that using single or multiple sessions of anodal tDCS or high-frequency rTMS to increase excitability of the left DLPFC could significantly improve dual-task performance for healthy adults and elderly people as well as patients of stroke and Parkinson disease [14, 42–44]. Third, neuroimaging evidence suggests that activation of the left DLPFC increases during the performance of dual-tasks, especially when one or both tasks require verbalization [45–48]. In our study, the cognitive task required participants to give consecutive verbal responses within one minute. Thus, we included children with hemiplegic and diplegic CP with mild motor impairments and excluded those with severe damage to the left DLPFC confirmed by MRI.

Studies have shown that despite a significant increase in PFC activation to recruit more cognitive resources, children with CP continued to have significantly reduced cognitive and motor performance while performing dual-tasks compared to typically developed peers [6]. This suggest a reduction in the efficiency of the PFC neural network execution, which is consistent with findings of increased PFC activation and inefficiency of the neural network during dual-tasks in healthy adults and elderly people [11]. A few studies that have applied M1-tDCS for 3–5 consecutive days have been able to induce cumulative effects, leading to an approximate enhancement of 20–40% in total motor learning when compared to sham stimulation [49, 50]. Deng et al. used 10 Hz rTMS for 3 consecutive days targeting the parietal cortex of 46 healthy adults and showed that rTMS was effective in improving their performance on a spatial spanning task [51]. Accordingly, in this study we only employed 3 consecutive days of 5 Hz rTMS to the left DLPFC in children with CP in order to improve their dual-task performance.

Liang et al. assessed the reliability and validity of BBT for children with CP, finding that improvements over 5.29 blocks in BBT could signify clinically meaningful changes in daily motor activities [34]. In our study, we observed an average improvement of 6.41 blocks in the BBT under the dual-task condition from the baseline after 3 sessions of active rTMS. While this change exceeds the threshold for clinical meaningfulness proposed by Liang et al. [34]., we acknowledge that the absence of a significant between-group difference limits definitive conclusions about rTMS-specific effects. Nevertheless, the magnitude of improvement suggests potential clinical relevance warranting further investigation in larger controlled trials. In our study, active rTMS did not result in significant improvements in BBT scores under the single-task condition compared to sham rTMS. Although rTMS targeting the motor cortex has been proved to improve hand function in children with CP [20, 21]. A recent systematic review has provided moderate certainty evidence that active rTMS likely yields minimal to no difference in unimanual dexterity, as measured by the BBT, compared to sham rTMS in children with CP [52]. Previous studies have indicated that tDCS does not improve performance in standing, walking in older adults under the single-task condition [14, 42, 43]. These studies also revealed that reductions in dual-task cost are specifically spurred by improved performance under the dual-task condition. In our study, we observed a significant reduction in dual-task cost to BBT only after 3 sessions of active rTMS. This was due to the fact that BBT scores achieved higher improvement under the dual-task condition than the single task condition. This suggests that active rTMS targeting the left DLPFC did not improve hand dexterity in children with CP compared to sham rTMS. But active rTMS may improve participants’ capacity to recruit available cognitive-motor resources or efficiently allocate more resources to each task while performing dual-task with their more affected hand.

In the active rTMS group, the changes from baseline in SST scores under the dual-task condition on days 2 and 3 showed significantly greater improvements compared to the sham group. Ljubisavljevic et al. evaluated the effect of anodal tDCS on the left DLPFC in healthy older adults by combining a cognitive task (Serial-7) with a hand dexterity task, separately assessing cognitive and motor aspects [13]. Their findings indicated an improvement in cognitive performance under dual-task conditions [13]. tDCS on the left DLPFC could improve early-phase manual dexterity skills with the non-dominant hand in healthy young adults, and its effectiveness depended on the increased cognitive demands of the target task [53]. Our results were consistent with these findings, indicating the effectiveness of rTMS on the DLPFC for improving cognitive functions. Furthermore, our study showed that active rTMS induced greater improvements in SST scores under the single-task condition when compared to sham rTMS on day 3. Several studies have examined the effect of NIBS applied to the left DLPFC on the dual-task performance in stroke patients and healthy elderly; the results indicated that NIBS had no impact on cognitive performance under the single-task condition [14, 42]. This inconsistency may be attributed to the fact that most of these studies implemented a single-session intervention, which precludes the potential for cumulative treatment effects. Our study observed that the effect of rTMS on SST performance emerged on day 3, indicating that single-session stimulation may be limited in effectiveness and that multiple sessions are required to achieve significant improvements. Overall, the results of our study showed that rTMS was effective in improving cognitive task performance under the dual-task as well as single-task conditions. This may be attributed to the fact that the targeted area of the stimulation is primarily associated with cognitive functions. However, we did not observe a positive effect on reducing dual-task cost to SST scores after 3 sessions of active rTMS. This might because the improvement of SST scores in the single-task condition (14.26 numbers) was more pronounced than that in the dual-task condition (9.36 numbers) on day 3.

Participants in our study were MACS levels I-II with mild functional impairments. All participants had normal or borderline social life skills and were similar to children of the same age in terms of living, learning and socialization. Repeated assessments of the results (6 total per task) likely contributed to performance improvements in both groups, especially for these children with mild impairments. Therefore, these improvements may be partially attributed to learning and practice effects. Previous studies that examined task performance under dual-task condition showed that the performance depends on the priority given to each of the tasks [54]. Prioritization may be determined by the motivation to minimize danger and maximize pleasure [54]. Most of the previous studies examined gait or postural task in children with CP, in which a “posture-first” strategy is consciously or unconsciously employed to minimize the possibility of falling [5–8]. In our study, the participants were seated, thus excluding the “pressure” to prioritize motor task. Some earlier studies did not give specific instructions regarding task prioritization, while in our study participants were specifically instructed and repeatedly reminded not to priorities any task. Additionally, in our study, all participants were cognitively normal CP children with mild motor impairments and demonstrated good compliance through pre-test training. This may, to a certain extent, prevent them from overusing a certain strategy. More importantly, there were no significant differences between dual-task cost to BBT scores and SST scores in the active rTMS group or the sham group. The results indicate that participants in either group did not excessively adopt a cognitive-first or motor-first strategy, suggesting balanced initial resource allocation between motor and cognitive tasks in both groups.

Our findings provide new evidence that bridges the existing knowledge gap on the impact of rTMS on dual-task performance and highlight the crucial role of the left DLPFC in further studying the neural mechanism underlying dual-task activities in children with CP. Strategies that enhance the activation of DLPFC, such as combining dual-task training with brain stimulation, might be more beneficial for improving dual-task performance in children with CP. Additionally, although we have compared the difference in changes from baseline between the two groups using appropriate statistical methods with baseline scores included as covariates in the analysis to evaluate robustness, the substantially better baseline performance of the sham group may make it more susceptible to ceiling effects. This might, to some extent, limit the potential for improvement in their performance, thereby potentially masking the true effects of the intervention.

Our study demonstrated well tolerability of rTMS in children, with all 40 children (totaling 120 treatment sessions) completing the trial without any serious adverse event. We observed only mild, transient adverse events (2 cases of scalp discomfort and headache in the active group and 2 cases of headache in the sham group), all of which were self-remitting within a few minutes post-treatment. This reinforces the safety and tolerability of rTMS in children with CP as demonstrated in prior studies [18, 55, 56]. Mild TMS-related headache was reported in 40% of children with perinatal stroke as compared to 13% of healthy children in a study reporting data from 3.5 million stimulations [55].

Limitations and future directions

This study has several limitations. First, the modest sample size and lack of follow-up assessments make it difficult to evaluate if the beneficial effects observed are sustained or decayed over time. Future research should incorporate longitudinal designs with follow-up assessments to determine the longevity of effects. Second, no method was used to assess or control for strategy (e.g., motor-first vs. cognitive-first) and participants with CP included in the study were relatively mild impairments. Future research is needed to record kinesiological data to fully evaluate the motor patterns of participating children. Having this data would help us determine whether children employed a motor-first or cognitive-first strategy. Third, physiological evidence that underlies the behavioral data is lacking. The interpretation of the underlying mechanisms by which rTMS improves dual-task performance in children with CP remains speculative in this study. An individualized brain stimulation approach, such as employing functional near-infrared spectroscopy (fNIRS) or functional magnetic resonance imaging (fMRI) for personalized targeting based on the identification of subject-specific brain regions, might further enhance the therapeutic effect of rTMS and establish clearer relationships between cortical activation mapping and behavioral effects.

Conclusion

This study demonstrated that rTMS applied to the left DLPFC was safe and effective in improving the performance of cognitive-motor dual-task in children with CP. Further research with larger samples and an evaluation of long-term effects are warranted.

Author contributions

Jingyi Zhao: Conceptualization, Methodology, Formal analysis, Investigation, Writing - original draft. Tingting Peng (Senior, 1996): Conceptualization, Methodology, Data curation, Project administration. Liru Liu: Conceptualization, Investigation. Lu He: Conceptualization, Resources, Supervision, Project administration. Jingbo Zhang: Investigation, Writing-Review & Editing. Yuan Zhang: Investigation, Formal analysis. Qingfen Hou: Investigation. Hongyu Zhou: Writing-Review & Editing. Xubo Yang: Conceptualization. Kaishou Xu: Conceptualization, Methodology, Funding acquisition, Project administration, Writing– review & editing, Supervision.

Funding

The work was supported by STI 2030—Major Projects (No. 2021ZD0200500), National Natural Science Foundation of China (82472598), the Natural Science Foundation of Guangdong Province (2025A1515010379), the Featured Clinical Technique of Guangzhou (2023 C-TS59), Guangzhou Municipal Science and Technology Project (2024A03J01274), and Plan on enhancing scientific research in Guangzhou Medical University (GMUCR2024-02020). The funders played no role in the design, conduct, or reporting of this study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Guangzhou Women and Children’s Medical Center. Written informed consent was obtained from the legal guardians of each participant before enrollment.

Consent for publication

Written informed consent for publication was obtained from the participants involved in the study.

Competing interests

The authors declare no competing interests.