Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized controlled trial

Authors


Abstract

Aim

The aim of this study was to determine the feasibility and efficacy of five treatments of 6 Hz primed, low-frequency, repetitive transcranial magnetic stimulation (rTMS) combined with constraint-induced movement therapy (CIMT) to promote recovery of the paretic hand in children with congenital hemiparesis.

Method

Nineteen children with congenital hemiparesis aged between 8 and 17 years (10 males, nine females; mean age 10 years 10 months, SD 2 years 10 months; Manual Ability Classification Scale levels I-III) underwent five sessions of either real rTMS (n=10) or sham rTMS (n=9) alternated daily with CIMT. CIMT consisted of 13 days of continuous long-arm casting with five skin-check sessions. Each child received a total of 10 hours of one-to-one therapy. The primary outcome measure was the Assisting Hand Assessment (AHA) and the secondary outcome variables were the Canadian Occupational Performance Measure (COPM) and stereognosis. A Wilcoxon signed-rank sum test was used to analyze differences between pre- and post-test scores within the groups. Analysis of covariance was used to compute mean differences between groups adjusting for baseline. Fisher's exact test was used to compare individual change in AHA raw scores with the smallest detectable difference (SDD) of 4 points.

Results

All participants receiving treatment finished the study. Improvement in AHA differed significantly between groups (p=0.007). No significant differences in the secondary outcome measures were found. Eight out of 10 participants in the rTMS/CIMT group showed improvement greater than the SDD, but only two out of nine in the sham rTMS/CIMT group showed such improvement (p=0.023). No serious adverse events occurred.

Interpretation

Primed, low-frequency rTMS combined with CIMT appears to be safe, feasible, and efficacious in pediatric hemiparesis. Larger clinical trials are now indicated.

Abbreviations
AHA

Assisting Hand Assessment

CIMT

Constraint-induced movement therapy

COPM

Canadian Occupational Performance Measure

IHI

Interhemispheric inhibition

MEP

Motor evoked potential

rTMS

Repetitive transcranial magnetic stimulation

SDD

Smallest detectable difference

In the last two decades, constraint-induced movement therapy (CIMT) with an emphasis on motor training of the affected limb, coupled with constraint of the unaffected limb, has been employed in stroke rehabilitation.[1] CIMT intervention has been studied in the pediatric population with hemiparesis, with improved functional outcomes noted in the affected upper extremity.[2] The potential for enhanced motor performance may occur with synergistic application of behavioral and electrophysiological interventions.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation procedure involving a rapidly changing magnetic field that induces electrical currents within the cortex. Historically, TMS has been used as a test for brain excitability.[3] More recently, investigators have also used TMS repetitively as an intervention to modulate brain excitability and improve motor function. High-frequency rTMS, defined as a stimulation rate greater than 1 Hz, produces an excitatory after effect.[4] Conversely, low-frequency rTMS, defined as a stimulation rate less than or equal to 1 Hz, depresses excitability.[5]

Interhemispheric inhibition (IHI) is a normal physiological interaction between the two hemispheres of the brain. For example, the primary motor cortex of one hemisphere suppresses activity of the contralateral primary motor cortex via transcallosal connections and the action of gamma-aminobutyric acid interneurons.[6] Exaggerated IHI has been found in adult stroke patients,[7] with excessive inhibition of the lesioned cortex by the non-lesioned cortex inhibiting the activity of surviving neurons. With regard to the typical age at development of interhemispheric inhibition, Heinen et al. found that it was not present in healthy pre-school children at a mean age of 4 years 7 months,[8] but that it was present in healthy children in the age range of 10 to 15 years.[9] In children with congenital hemiparesis, abnormal persistence of projections from the non-lesioned cortex to the paretic hand may also contribute to limitations of function.[10] Therefore, the potential exists for an imbalance of IHI in pediatric hemiparesis as well as the preserved developmental connectivity of the contralesional hemisphere with the paretic hand. Accordingly, two possible routes exist for rebalancing the interaction between hemispheres and increasing the excitability of viable but dormant neurons in the ipsilesional primary motor area: (1) high-frequency rTMS to the ipsilesional primary motor cortex or (2) low-frequency rTMS to the contralesional primary motor cortex.[11]

An innovative approach to intensify the desired treatment effect of rTMS is to include priming. The rationale for priming is based on the work of Iyer et al.[12] By enhancing the excitatory level of the cortex membrane, a paradoxical effect of enhanced subsequent inhibition may occur. In order to enhance the effect of inhibiting the exaggerated IHI arising from the contralesional hemisphere, priming the brain before low-frequency rTMS can also be incorporated.[12] This ultimately disinhibits the ipsilesional hemisphere. Demonstration of the safety of single treatments of 6 Hz primed low-frequency rTMS in adults with stroke has been reported.[13] Thus, the aims of this study were to examine the safety, feasibility, and efficacy of a synergistic intervention using 6 Hz primed low-frequency rTMS to the contralesional primary motor cortex and CIMT in children with hemiparesis.

Method

Participants

Nineteen children aged 8 to 17 years (mean age 10y 10mo; SD 2y 10mo) with congenital hemiparesis due to stroke or periventricular leukomalacia were recruited from the Gillette Children's Specialty Healthcare and/or through mailings, community- and school-based contacts, and diagnosis-specific website postings between 2009 and 2012 (Table 1). This sample size for our phase 1 clinical trial was based on the work by Kirton et al.[14] Other inclusion criteria included at least 10° of active finger movement and the presence of a motor evoked potential (MEP) from the ipsilesional primary motor cortex. Children were excluded if any of the following were appropriate to them: metabolic disorders, neoplasm, seizure within the past 2 years, botulinum toxin (BoNT) treatment or phenol block within the previous 6 months, disorders of cellular migration and proliferation, hemorrhagic brain lesion, receptive aphasia, pregnancy, indwelling metal or gross visual field cuts, or current involvement in a formal rehabilitation program. Children were also excluded if an MEP could not be found in the ipsilesional hemisphere.

Table 1. Participant characteristics
ParticipantGroupSexAge (y)Stroke locationSide of hemiparesisManual Ability Classification Scale level
  1. Participants are listed in the two groups: real rTMS/mCIMT and sham rTMS/mCIMT. F, female; BG, basal ganglia; LV, lateral ventricle; R, right; M, male; ALIC, anterior limb internal capsule; PLIC, posterior limb internal capsule; T, thalamus; P, putamen; CS, centrum semiovale; MCA, middle cerebral artery; IC, internal capsule; LN, lentiform nucleus; GP, globus pallidus; CR, corona radiata; PVWM, periventricular white matter; C, caudate; L, left.

1RealF15BG, LVRII
2RealM8ALIC, PLIC, T, PRII
3RealM8ALIC, T, P, CSRII
4RealM8MCA frontal parietal lobesRII
5RealF12MCA frontal parietal, BG, TRII
6RealM9IC, T, P, LN, GP, CR, PVWMRII
7RealM11Frontoparietal cortex, IC, T, C, P, CSRII
8RealF15MCA to frontal lobeLI
9RealF11R post frontal lobe, CSLII
10RealF13CS, T, BGRII
11ShamF15PVWMLI
12ShamM8MCA, CSRI
13ShamM8ALIC, T, P, BGRII
14ShamM12BG, T, CSLII
15ShamF8Posterior frontal lobe, CR, CSLII
16ShamF8CS, PLIC, T, C, PRII
17ShamM16CR, T, BGRII
18ShamF11MCA frontal temporal parietal lobesRIII
19ShamF15CS, T, BGLI

This study was a randomized, controlled, blinded, pre-test–post-test trial comparing active and sham rTMS in combination with CIMT (Fig. 1). Legal guardians gave written consent and all children gave written assent to the study. The study was approved by the US Food and Drug Administration, the University of Minnesota and Gillette Institutional Review Board, the Clinical and Translational Science Institute, and the Center for Magnetic Resonance Research.

Figure 1.

Consolidated standards of reporting trials (CONSORT) diagram. MRI, magnetic resonance imaging; HIPAA, Health Insurance Portability and Accountability Act; MEP, motor evoked potential; rTMS, repetitive transcranial magnetic stimulation; CIMT, constraint-induced movement therapy.

Procedures

A magnetic resonance imaging (MRI) session included fluid attenuation inversion recovery and gradient echo sequences for identification of the location and lesion type by the pediatric neurologist of the study. After therapist screening and physician assessment and approval, children received single pulses of TMS to the ipsilesional primary motor cortex to confirm the presence of an MEP, evidenced by electromyographic (EMG) monitoring from the affected extensor digitorum muscle. If a resting motor threshold could not be obtained, an attempt to measure the active motor threshold was then instituted. If neither was found, the participant was excluded from the study for consistency of investigating those children with intact crossed corticospinal tract integrity. Nineteen participants meeting our criteria were randomized, using a random numbers table, to one of two groups: rTMS/CIMT or sham rTMS/CIMT. Before entry in the study, participant numbers were assigned, without blocking, to the real rTMS group if the next number in the random numbers table was even. The participants were assigned to the sham rTMS group if the next number was odd. Baseline and outcome testing sessions occurred during a pre-test interval 2 days before the intervention, and again during a post-test session 2 days after the intervention. Researchers administering the rTMS interventions were not blinded. Testing researchers, physicians, caregivers, and participants were blinded to the treatment allocation.

rTMS/CIMT

This group received five treatments of real rTMS and five treatments of CIMT on alternate weekdays for 2 weeks. Participants were seated in a reclining chair, and wore a swim cap for marking stimulation points. A 70 mm figure-of-eight TMS coil connected to a Magstim 200 stimulator (Magstim Company Limited, Dyfed, UK) was held, by hand, over the approximate hotspot area for the contralesional primary motor cortex, tangential to the scalp, and orientated with the handle pointing posterolaterally at a 45° angle to the sagittal line. It was moved systematically to find the hotspot. Single-pulse magnetic stimuli were delivered at approximately 0.1 Hz, starting at an intensity of 50% of the stimulator maximum. This level was adjusted systematically until the resting motor threshold was found, defined as the minimum intensity required to elicit MEPs greater than or equal to 50 μV peak-to-peak in at least three out of five trials with the target muscle at rest. Occasionally, a mild active contraction in the target muscle was needed to elicit an MEP. Responses from the unaffected extensor digitorum muscle were monitored using electrodes connected to a Cadwell Sierra Wedge EMG amplifier (Cadwell Laboratories, Kennewick, WA, USA).

Once the hotspot and threshold were established, the child received priming rTMS followed by 1 Hz rTMS to the contralesional primary motor cortex with a Magstim Rapid[2] stimulator (Magstim Co.). Priming consisted of 10 minutes of 6 Hz rTMS at 90% of resting motor threshold, delivered in two trains per minute with 5 seconds per train and 25-second intervals between trains (a total of 600 priming pulses). Priming was followed immediately by an additional 10 minutes of 1 Hz rTMS at 90% of resting motor threshold without interruption (a total of 600 low-frequency pulses). During rTMS, EMG activity monitored the extensor digitorum plus the biceps brachii, the first dorsal interosseous, and the gastrocnemius muscles of the unaffected side for early signs of a possible seizure.[15]

On alternate days, children in this group received CIMT to the affected upper extremity. A univalve long-arm cast was fitted and applied to the unaffected hand and arm, from axilla to the tips of the fingers. The cast remained on 24 hours per day, except for 1 hour during the rTMS treatments (a total of 5 hours), when the cast was temporarily removed allowing for range of motion and skin integrity checks, neurological examination, washing, and attachment of electrodes for that rTMS session. CIMT treatments were performed for 2 hours with a trained therapist on the next weekday after the rTMS treatment. The CIMT treatments consisted of shaping and repetitive activities for function, range of motion, and strengthening of the affected upper extremity. The constraint cast was applied on treatment day 2, and removed on treatment day 10 (the cast was worn for a total of 13 days including weekends). Children continued to use their affected limb during home functional activities and a documented caregiver-supervised the home program.

Sham rTMS/CIMT

These children received the same intervention as the real rTMS/CIMT group except that a sham rTMS coil (Magstim Co.) was used to mimic the sound and tactile sensation of the rTMS without stimulation.

Outcome measurements

We incorporated the body function/structure and activity/participation domains of the International Classification of Functioning, Disability and Health.[16]

Primary outcome measure

The Assisting Hand Assessment (AHA) is a test for children with unilateral upper limb dysfunction which assesses body function and activity and is based on observing a child's spontaneous performance in bimanual functional activities.[17] This test uses an assessment through a standardized video-recorded play session. Activity is assessed on 22 items using a 4-point rating scale. The range of raw scores is 22 to 88 points, with higher scores indicating better ability. A Rasch analysis was used to convert the ordinal data to equal interval measures. The intraclass correlation coefficient (ICC) revealed excellent interrater (ICC=0.97) and intrarater (ICC=0.99) reliability[18] and it has been found to have high validity in use with children.

Secondary outcome measures

The Canadian Occupational Performance Measure (COPM) is an individualized outcome measure used to detect changes in the self-perception of the client's performance and satisfaction over time by identifying difficulty in the performance of activities of daily living.[19] The tool is a self-reported ordinal scale score and encompasses domains in impairments, body structure, activity, activity limitations, participation restrictions, and environmental factors that an individual experiences. Using this tool, the participants determined many of the treatment and functional goals which guided therapy sessions. Test–retest reliability has been found to be strong in the domains of performance (r=0.89) and satisfaction (r=0.88).[20]

The 12-object stereognosis test evaluates the ability to identify 12 different common objects through touch, placed individually in the blindfolded person's hand. In a study of 40 children with spastic hemiparesis, 97% had deficits in stereognosis, with an average of 5 out of 12 objects correctly identified in the affected hand.[21] A recent study by Kinnucan et al.[22] found that in 41 children (age range 6–16 y), impairment of 12-object stereognosis correlated with impairment in motor function.[22] Scores were significantly lower for the affected hand than for the less affected hand.

Finger extension force was assessed using a load cell with the voltage signal directed to a computer (WinDaq, Akron, OH, USA). Maximum finger extension force in newtons (N) was determined as the peak of the three trials performed during the testing session.

Statistical analysis

Medians and interquartile ranges, along with means and standard deviations, were computed for continuous variables. Frequencies and percentages were computed for categorical variables. A Wilcoxon signed-rank sum test was used to analyze pre-test and post-test differences. Because of baseline differences in both the raw and AHA unit scores, an analysis of covariance (ANCOVA) was performed to compare the pre- to post-test change in logit-based AHA units between the two groups while controlling for the baseline values. Residuals versus predicted values and normal probability plots were used to evaluate the assumptions of the ANCOVA. Owing to the small size of the pilot study, a Wilcoxon signed-rank sum test was also computed to compare the pre-/post-test change using non-parametric methods. Fisher's exact test was computed to compare AHA raw scores and logit-based AHA units exceeding the smallest detectable difference (SDD) of four raw score points and five logit-based AHA units, respectively.[23] No formal power analysis was completed: the sample size of 30 was planned, after a similar study. All tests were two-sided and no adjustment was made for multiple comparisons.

Results

Nineteen children with hemiparesis completed the study (10 males, nine females; mean age 10 y 10 mo, SD 2 y 10 mo, range 8–17 y; Manual Ability Classification Scale levels I-III; Table 2). Although the intended sample size was larger, the strict inclusion and exclusion criteria and an attempt to maintain the homogeneity of this sample meant that only 19 children were included. No serious adverse events were reported; the most common minor adverse events were self-limiting headache, which resolved within 24 hours after rTMS, and cast irritation.

Table 2. Baseline demographic, clinical, and outcome data comparing groups with adjustment for the corresponding baseline measure using ANCOVA
Demographics and baselinerTMSSham p
  1. A Wilcoxon signed-rank sum test was used to compare continuous measures and a Fisher's exact test was used to compare categorical measures. ANCOVA, analysis of covariance; rTMS, repetitive transcranial magnetic stimulation.

n 109 
Age (y)  0.90
Median (first quartile, third quartile)10 y 6 mo (8 y 2 mo 12 y 0 mo)10 y. 0 mo (8 y 0 mo 14 y 0 mo)
Mean (SD)10 y 9 mo (2 y 8 mo)10 y 10 mo (3 y 1 mo)
Sex (%)  0.66
Female4 (40)5 (56)
Male6 (60)4 (44)
Side of hemiparesis (%)  0.35
Left2 (20)4 (44)
Right8 (80)5 (56)
Manual Ability Classification Scale level (%)  0.17
I1 (10)3 (33)
II9 (90)5 (56)
III0 (0)1 (11)
Assisting Hand Assessment (AHA)
Raw score  0.53
Median (first quartile, third quartile)56 (50, 68)64 (56, 65)
Mean (SD)59 (13)64 (14)
Logit-based AHA units  0.54
Median (first quartile, third quartile)57 (50, 70)66 (57, 67)
Mean (SD)59.4 (15.0)66.9 (18.0)
Canadian Occupational Performance Measure
Performance score  0.44
Median (first quartile, third quartile)3.0 (2.4, 3.6)2.6 (2.0, 2.8)
Mean (SD)3.0 (1.1)2.6 (1.0)
Satisfaction score  0.61
Median (first quartile, third quartile)2.6 (2.4, 3.2)2.8 (1.8, 2.8)
Mean (SD)2.9 (1.2)2.5 (1.1)
Stereognosis score  0.69
Median (first quartile, third quartile)9.0 (4.2, 12.0)11.0 (3.0, 12.0)
Mean (SD)8.3 (3.7)8.0 (4.5)
Peak force (N)  0.89
Median (first quartile, third quartile)4.4 (3.4, 5.7)3.9 (3.6, 4.4)
Mean (SD)5.1 (2.9)5.1 (2.9)

Primary outcome measure

Table 3 shows the results of the analysis of the AHA ordinal raw scores and the interval logit-based AHA units.[23] Using a Wilcoxon signed-rank sum test, pre- to post-test improvement in hand function, as measured by the AHA raw score, was found to be significantly higher in the rTMS/CIMT group than in the sham rTMS/CIMT group (p=0.008). Using an ANCOVA, we regressed the pre–post AHA unit change on the treatment factor and the pre-logit-based AHA unit, which resulted in an adjusted mean difference between the rTMS and the sham group of 3.67 units (95% confidence interval 0.36–7.0 units; p=0.032). Using the SDD of the AHA raw score, 8 of 10 participants in the rTMS group had an improvement of 4 or more compared, with 2 of 9 in the sham group (p=0.023). In comparison, using the SDD of the AHA units, 9 of 10 of the rTMS group had an improvement of 5 or more, compared with 3 of 9 in the sham group (p=0.020).

Table 3. Outcome measures
OutcomesrTMS, mean change (SD)Sham, mean change (SD)rTMS vs sham (ANCOVA) p
  1. ap-value for mean change difference between treatment groups adjusting for baseline values in ANCOVA. bp-value from Fisher's exact test. rTMS, repetitive transcranial magnetic stimulation; AHA, Assisting Hand Assessment; SDD, smallest detectable difference.

Assisting Hand Assessment
Raw score5.6 (2.8)1.9 (2.0)3.45 (1.02–5.87)0.008a
Logit-based units6.7 (2.8)3.0 (3.6)3.67 (0.36–6.97)0.032a
Canadian Occupational Performance Measure
Performance score2.8 (1.7)2.9 (2.0)0.079 (–1.82–1.98)0.93a
Satisfaction score2.7 (2.2)2.7 (1.8)0.17 (–1.92–2.27)0.86a
Stereognosis score1.0 (1.3)0.22 (1.4)0.80 (–0.53–2.13)0.22a
Peak force (N)3.4 (3.9)3.9 (3.2)−0.54 (–5.22–4.15)0.80a
AHA SDD
Raw score change ≥ SDD of 4, % (n)80 (8)22 (2)0.023b
Logit-based AHA units change ≥ SDD of 5, % (n)90 (9)33 (3)0.020b

Secondary outcome measures

No significant pre-post differences were observed between groups in the COPM performance, COPM satisfaction, 12-object stereognosis, and finger force measures, each adjusted for the corresponding pre-test value. However, for both the COPM performance and COPM satisfaction subsections, the mean change in both groups was greater than the 2.0-point change considered necessary to constitute a minimal clinically important difference.[19] Minimal clinically important difference values were not established for the 12-object stereognosis test, or for finger extension force (Fig. 2).

Figure 2.

Effect of primed low-frequency repetitive transcranial magnetic stimulation (rTMS) and constraint-induced movement therapy (CIMT) on primary and secondary outcome measures. Primary outcome measure: Assisting Hand Assessment (AHA). (a) Raw score; (b) scaled score. Significant differences noted in both scoring types between groups. Secondary outcome measures: Canadian Occupational Performance Measure (COPM). (c) Performance score; (d) satisfaction score; (e) stereognosis; and (f) force. There were trends toward improvements in both groups from pre-test to post-test.

Discussion

To our knowledge, only one other study has investigated the application of rTMS in children with hemiparesis.[14] None has examined the use of 6 Hz priming of low-frequency rTMS, nor have any investigated the combined intervention of rTMS and CIMT with children.

In this study, a significant between-group difference was found in our primary outcome measure, the AHA, with those receiving real rTMS showing greater improvements, adjusted for baseline differences. Although the treatment assignment was randomized, a difference between the two groups of 9 AHA units at baseline was evident, potentially complicating the interpretation of the results. Both the AHA ordinal raw scores and interval AHA units revealed that significantly more participants achieved the SDD in the real rTMS/CIMT group. The finding of significant within-group pre- to post-test improvements in both groups is consistent with a recent randomized controlled trial of CIMT in children.[24] However, combining 6 Hz priming of low-frequency rTMS with CIMT appears to provide an added benefit above and beyond CIMT alone, and this benefit was at a meaningful level for this group.

Although within-group improvements were noted in some secondary outcomes, there were no significant between-group differences. All children received CIMT. With regard to the COPM, the possibility exists that, with our small sample size, the sensitivity of this tool in detecting a difference from rTMS, beyond the potential influence of CIMT alone, was weakened. For the finger force test, limitations existed in attaining the proper test position, which may have influenced the validity of our results. For stereognosis, the possibility exists that our statistical power for this test was too low to detect a real effect or that stimulation over the motor cortex does not specifically affect the sensory system associated with stereognosis. Further trials with a larger sample and investigation of the longitudinal effect on this system are indicated.

Clinical implications

The significant between-group difference in this study necessitates continued investigation of the use of rTMS in combination with behavioral rehabilitation in children with hemiparesis. Consideration of both sensory and motor evaluation may allow greater appreciation of the influence of this intervention.

As mentioned, one of the exclusion criteria in this study was the absence of an MEP when using TMS to investigate the motor threshold of the ipsilesional hemisphere. By including only children who showed an ipsilesional MEP, we assumed integrity of the crossed corticospinal tract. Therefore, the significant results noted in this study may have been a result of increased excitability of the ipsilesional primary motor cortex owing to decreased IHI from the contralesional hemisphere. Additionally, neurogenic changes could have occurred through the influence of neurotrophic factors such as brain-derived neurotrophic factor, a protein acting to preserve nerve function and support nerve growth.[25] The potential for alteration of gene expression may also have contributed to the reorganization and gains in motor function seen.[26]

Further investigation, imaging, and TMS excitability testing and mapping may reveal the neurological underpinnings of this potential reorganization and provide information on responders to this intervention in the clinical setting.

Limitations

The small sample size in this study is a limitation for generalizing the results to a larger, more validating sample. This study was an exploratory phase I clinical trial with no formal power analysis performed. We were guided by the only other trial at the time employing rTMS in pediatric hemiparesis,[14] which used 10 participants. CIMT alone has been shown to contribute to significant changes in motor and sensory function in both adult and child populations.[2, 27] It, therefore, remains valuable to understand what treatments may have an effect, especially as optimal dosing for CIMT has not been established. As the children in this study were casted continuously, there was also the potential for indirect therapy when not receiving direct rehabilitation, such as when performing activities of daily living. The majority of the testing sessions (24 of 38), were scored by the same therapist although, owing to unforeseen circumstances, we needed to employ other testers. All testers were AHA certified and pre- and post-testing of each child was carried out by the same tester. A follow-up group assessment was not a component of the research design, and conclusions regarding long-term effects cannot be made.

Future research

In brain injury, rTMS is emerging as a possible important adjuvant to behavioral therapy. Many questions remain to be answered, however, including the most appropriate patients to receive rTMS, the optimum time between rTMS and therapy, and the optimum dosage of rTMS. For the first time, we have explored the use of primed rTMS in children with stroke. The rationale for priming is based on the Bienenstock–Cooper–Munro theory of bidirectional synaptic plasticity,[28] which emphasizes that plasticity depends on the recent history of activity at a synapse. Indeed, in healthy participants, excitatory conditioning deploys mechanisms that magnify the effects of subsequent depressive conditioning,[12] which is thought to maintain synaptic activity within a stable range (i.e. homeostatic plasticity). Thus, we used excitatory (6 Hz) conditioning of the contralesional primary motor cortex followed by depressive (1-Hz) conditioning to depress more strongly the IHI from the contralesional primary motor cortex acting on the ipsilesional primary motor cortex. With safety, feasibility, and preliminary efficacy of primed rTMS now demonstrated in children with stroke, next it is important to compare directly primed versus unprimed rTMS to confirm the value of priming. Imaging and cortical mapping would provide increased understanding of appropriate applications in specific participant populations or optimal patient populations with a range of manual hand control and function.

Conclusion

This study investigated the treatment effect of the combined use of an electrophysiological intervention applied to the brain and a behavioral intervention in children with hemiparesis. The intervention applied revealed significant functional outcomes and was well tolerated, suggesting that the synergistic effect of rTMS and CIMT has the potential to improve the efficacy of neurorehabilitation applications in this population.

Acknowledgements

This study is registered on clinicaltrials.gov (NCT01104064) of the United States National Institutes of Health. This study was funded by NIH grant number 1 RC1HD063838-01. This publication (or project) was also supported by grant number 1UL1RR033183-01 from the National Center for Research Resources and by grant number 8 UL1 TR000114-02 from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CTSI or the NIH. The University of Minnesota CTSI is part of a national Clinical and Translational Science Award consortium created to accelerate laboratory discoveries into treatments for patients. The University of Minnesota Center for Magnetic Resonance Research funding supported the imaging work number P41 EB015894. Bernadette Gillick was supported by the Foundation for Physical Therapy Promotion of Doctoral Studies and the American Academy of Cerebral Palsy and Developmental Medicine Student Travel Award during this thesis work. We also acknowledge the assistance of the physical therapy graduate students Sarah Ellsworth, Layla Elmajri, and Emily Henneman. We are grateful for the inspiring children and families who dedicated their time to participating in this study.

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