Single-pulse transcranial magnetic stimulation for assessment of motor development in infants with early brain injury

Abstract

Introduction:

Single-pulse transcranial magnetic stimulation (TMS) has many applications for pediatric clinical populations, including infants with perinatal brain injury. As a non-invasive neuromodulation tool, single-pulse TMS has been used safely in infants and children to assess corticospinal integrity and circuitry patterns. TMS may have important applications in early detection of atypical motor development or cerebral palsy.

Areas covered:

The authors identified and summarized relevant studies incorporating TMS in infants, including findings related to corticospinal development and circuitry, motor cortex localization and mapping, and safety. This special report also describes methodologies and safety considerations related to TMS assessment in infants, and discusses potential applications related to diagnosis of cerebral palsy and early intervention.

Expert opinion:

Single-pulse TMS has demonstrated safety and feasibility in infants with perinatal brain injury and may provide insight into neuromotor development and potential cerebral palsy diagnosis. Additional research in larger sample sizes will more fully evaluate the utility of TMS biomarkers in early diagnosis and intervention. Methodological challenges to performing TMS in infants and technical/equipment limitations require additional consideration and innovation towards clinical implementation. Future research may explore use of non-invasive neuromodulation techniques as an intervention in younger children with perinatal brain injury to improve motor outcomes.

Plain Language Summary:

Single pulse transcranial magnetic stimulation (TMS) is a safe and non-invasive way to study brain activity in infants and children who have experienced brain injuries around the time of birth. Infants who have had an early brain injury may develop cerebral palsy, a developmental disorder that affects movement. TMS uses a device that gives single pulses of energy to activate specific areas of the brain. This can be used to study how the brain connects to the muscles in the body through paths or ‘tracts.’ TMS helps researchers understand the development of the tracts and the potential need for therapy. This article reviews research studies that used TMS in infants and explains how TMS can be used to assess brain development. It also reviews safety considerations and challenges related to using TMS in infants. TMS could be a valuable tool for early diagnosis of cerebral palsy and could also help guide treatments for infants with brain injuries. However, more research is needed, using larger groups of babies, to potentially expand the use of TMS in clinical practice. Future directions include developing infant-specific research tools and using non-invasive brain stimulation to improve recovery for infants with brain injuries.

1. Introduction

Single-pulse transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique, offers myriad applications in cortical excitability and connectivity assessment across the lifespan. TMS can assess development and recovery in both adult and pediatric clinical populations with stroke and brain injury, including infants with brain injury occurring in the perinatal period (at or around the time of birth). Perinatal brain injury, including that resulting from mechanisms such as stroke, brain bleed, and hypoxic-ischemic encephalopathy, is a primary cause of cerebral palsy (CP) [1,2]. CP is the most common motor disability in childhood [3], and is associated with alterations in motor system and corticospinal development [4]. Recent guidelines highlight the importance of early detection and diagnosis of CP in infants, and subsequent access to early intervention [3]. TMS, as a non-invasive assessment of motor system integrity and plasticity, may have unique applications related to early detection and intervention for infants with perinatal brain injury who are at risk for CP.

This special report will describe methodologies, safety considerations, and limitations related to TMS assessment; summarize existing literature integrating single-pulse TMS for assessment of cortical excitability, integrity, and plasticity; identify potential applications related to diagnosis of CP and early intervention; and explore future directions for research and clinical implementation in the unique population of infants with perinatal brain injury.

2. Single-Pulse TMS Description

TMS utilizes an electromagnetic magnetic coil to produce a brief, high current pulse. The induced magnetic field can reach up to about 2 T, and typically lasts for about 100ms [5]. The changing primary current of the magnetic field induces secondary electric currents in human brain tissues. When stimulating over the motor cortex, TMS is believed to excite corticospinal tract (CST) projections, producing a motor evoked potential (MEP) in the target muscle that can be recorded via surface electromyography (EMG) [6]. Table 1 describes some of the common measurements obtained from single-pulse TMS, and how these metrics may be altered in infancy.

Table 1.

Definitions of common measurement terms associated with transcranial magnetic stimulation assessment and reported differences in infants.

Metric	Definition	Reported change in infants
Resting Motor Threshold (RMT)	Amount of current needed to evoke an MEP, measured as percentage of maximum stimulator output (%MSO). Provides information about electrophysiological maturation, reflects myelination and synaptic efficacy [7].	Lower at term age, rises to peak at 3 months of age, then decreases to reach adult-like levels in early adolescence [7,8].
MEP amplitude	Measure of corticospinal excitability [6].	Dependent on factors related to protocol and setup such as EMG placement and stimulation intensity, as well as intrinsic fluctuations in excitability [6].
Latency	Duration of time between TMS pulse delivery and MEP response. Dependent upon the muscle measured and the activity state [9,10].	Decreases with age [7], there is a greater difference between “active” muscle MEP latency and resting MEP latency in children than in adults [9].
Central Motor Conduction Time (CMCT)	CMCT is equivalent to the corticomotor latency (assessed with TMS to the motor cortex) – peripheral motor latency (estimated after stimulation of the proximal spinal nerve at level of intervertebral foramen) [11].	Decreases with age: Active CMCT reaches maturity within the first 3–5 years of postnatal life; resting CMCT does not reach maturity until early adolescence [9], likely due to increasing myelination and developing central motoneuronal recruitment [9,12,13].
Cortical Silent Period (CSP)	Transient suppression of voluntary muscle activation following TMS pulse delivery, in an active muscle. Likely influenced by spinal and supraspinal inhibitory mechanisms, including intracortical inhibitory mechanisms [14]. In infants, CSP has been used to assist in localizing the motor hotspot when an MEP was unable to be evoked [15].	Limited reporting of CSP duration in infants. No differences found in CSP duration in adults compared to children age 6–13 [7].

TMS = transcranial magnetic stimulation; MEP = motor evoked potential; EMG = electromyography

3. Methodological considerations for infants

3.1. Anatomical considerations for TMS

Infant brain and skull anatomy may influence the electric field induced by TMS compared to that in adults, and excitability differs across development. Modeling studies have demonstrated that brain volume, the width of the dural sinus, gyrus height, and sulcus width impact the strength of the electric field and the direction of current generated by TMS [16–19]. In infants, the resting motor threshold (RMT) for evoking MEPs appears to peak at around three months of age, which is consistent with corticospinal pruning occurring within the motor system during this time period [8]. RMT then decreases with age and reaches adult-like levels in early adolescence [7,8].

In adults with stroke or brain atrophy, the electric field generated by TMS can be influenced by increased conductivity of the lesioned tissue, due to replacement of necrotic brain tissue with CSF and glial fibers [20–22]. Near a lesion site, the current may be perturbed in magnitude, location, and orientation, resulting in decreases to both accuracy and precision of stimulation [21]. In children with stroke lesions, the electric field distribution has been found to have greater variability in the lesioned hemisphere than in the non-lesioned hemisphere [23]. Individual infant neuroanatomy, including lesion location and size, thus becomes an important consideration when interpreting cortical excitability testing and evaluating safety in infants with perinatal brain injury.

3.2. TMS administration considerations

Performing brain stimulation in the infant population requires special considerations and accommodations. Considerations for TMS safety are outlined in Section 4. Our team typically performs TMS with an infant seated in a caregiver’s lap. Stereotactic neuronavigation, integrating the infant’s T1 anatomical MRI, can assist to accurately localize TMS to cortical targets. When a T1 MRI is not available, age-appropriate pediatric templates may be used instead to localize the target region (e.g., motor cortex).

Selection of muscle groups for EMG should take infant size and motor development into consideration. Studies in infants have reported successfully obtaining MEPs from biceps [8,13,24–28], abductor pollicis brevis [15,29–32], brachioradialis [15,27], wrist flexors [33–35], hypothenar muscles (abductor digiti minimi) [13,24], and first dorsal interosseous [26] in the upper extremity; and abductor hallucis [29], vastus lateralis [36], tibialis anterior [15,30,31,36], hamstrings [36], and gastroc-soleus [36] in the lower extremity. Awake infants move frequently; therefore, MEPs may reflect either RMT or Active Motor Threshold (AMT), considering baseline EMG activity. Due to the higher RMT and the increased variability of response in infants, equipment and stimulation power limitations may reduce the ability to elicit an MEP [15]. Strategies reported to overcome the high RMT include starting assessment at higher stimulation intensities, timing the TMS pulse to periods of increased EMG activity, and using cortical silent period (CSP) instead of MEP to determine motor response [8,36,37].

4. Single-pulse TMS safety in infants

As with brain stimulation in individuals of all ages, safety is paramount. Existing evidence suggests that single-pulse TMS is safe in infants and children under the age of two years, as young as the neonatal period. Our review of the literature identified 23 publications to date that have reported the use of single-pulse TMS in infants and children under the age of two, including typically-developing children and children with neurological diagnoses (Table 2) [8,10,13,15,24–31,33–44]. Additionally, one case study incorporated repetitive TMS (rTMS) in an infant as an intervention for refractory epilepsy [32]. Across infant studies, when safety or tolerability outcomes were specifically reported (in 11 publications), TMS was determined to be well-tolerated. In one report, seizures occurred during or after TMS in about 20% of children with a refractory epilepsy diagnosis while undergoing pre-operative examination; these seizures were consistent with their usual clinical semiology [15]. No other serious adverse events were reported by any study. Safety findings are similar to larger-scale analyses of safety in older pediatric populations [45].

Table 2.

Summary of publications incorporating transcranial magnetic stimulation in infants

Authors	Year	Number of children <2 years	Youngest age assessed	Diagnosis	Adverse events and tolerability
Koh and Eyre [25]	1988	18	32 weeks gestation	Typically-developing	Well tolerated; no adverse events
Eyre et al. [24]	1991	unknown	32 weeks gestation	Typically-developing	None reported
Muller et al. [10]	1991	13 children <3 years	2 weeks	Typically-developing	None reported
Muller et al. [29]	1992	unknown	7 months	Hemiparesis of varied etiologies	None reported
Nezu et al. [41]	1997	6 children <3 years	1 year	Typically-developing	None reported
Tamer et al. [42]	1997	unknown	1 year	Typically-developing and malnourished	None reported
Eyre at al. [13]	2000	223	Neonates	Pre-term or term-born	None reported
Fietzek et al. [35]	2000	unknown	0.2 years	Typically-developing	None reported
Eyre at al. [8]	2001	18	Neonates	Typically-developing	None reported
Collado-Corona et al. [30]	2001	4	2 months	Varied	No impact of TMS on auditory function
Dachy and Dan [38]	2002	2	1 year	Spasticity	None reported
Geerdink et al. [39]	2006	13	Neonates	Spina bifida	All infants tolerated magnetic stimulation without discomfort
Eyre et al. [44]	2007	71	1.5 months	Typically-developing and acute brain lesions	None reported
Colon et al. [27]	2007	6	4 months	Obstetric brachial palsy	None reported
Dabydeen et al. [28]	2008	16	Neonates	Neonatal encephalopathy or white matter disease with prematurity	None reported
Santiago-Rodríguez et al. [31]	2009	30	3 months	Typically-developing and periventricular leukomalacia	None reported
Koudijs et al. [40]	2010	6	5 months	Intractable epilepsy	No adverse events occurred in children under 3; tolerated TMS without discomfort
Yang et al. [36]	2013	5	1 year	Hemiparetic cerebral palsy	Well tolerated. No adverse events reported during the study or at final follow-up
Narayana et al. [37]	2015	4	17 months	Variable developmental delays	No adverse events, no seizures
Narayana et al. [43]	2017	1	11 months	Seizure disorder	No TMS-induced seizures occurred
Nemanich et al. [34]	2019	6	3 months	Perinatal intracranial hemorrhage or stroke	No serious adverse events occurred. Stress responses observed included coughing, crying, and face redness. 24-hour phone follow-up confirmed no serious adverse events had occurred.
Kowalski et al. [33]	2019	10	3 months	Perinatal stroke, hemorrhage, or periventricular leukomalacia	No adverse events during assessment or reported by parents 24 hours post assessment. No adverse events reported at long-term follow-up 1–4 years later (Gillick Lab, unpublished data)
Narayana et al. [15]	2021	36	2 months	Refractory epilepsy, brain tumor	Motor mapping was usually well tolerated and experienced by most children as painless. 10 children had seizures during or after the mapping session; seizure semiology and duration observed during TMS were consistent with clinical seizures. Determined that the majority of seizures were unlikely to be TMS-induced, but rather represented the patient’s characteristic seizure pattern.
Chang et al. [32]	2022	1	10 months	Chronic progressive epilepsia partialis continua, POLG1 mutations	rTMS was used to interrupt seizures. Temporarily seizure relief can be achieved safely through rTMS.

TMS = transcranial magnetic stimulation, rTMS = repetitive transcranial magnetic stimulation

Published guidelines for TMS safety (e.g. International Federation of Clinical Neurophysiology safety recommendations [46]) include only limited information about safety in young infant populations. Furthermore, safety assessments implemented in existing studies, if present, are infrequently described in detail. Nemanich et al. reported monitoring vital signs, infant state, and stress responses before, during, and after the TMS testing session, and followed up with a caregiver 24 hours after assessment to document any changes in behavior [34]. Narayana et al. reported performing TMS sessions in infants and children with refractory epilepsy under nursing supervision, and monitored children visually and by EMG for signs of seizures or intracortical spread of excitation.

Careful screening of infants is necessary to ensure safety with TMS. Many infants with perinatal brain injury will experience seizures and be prescribed anti-seizure medications, which can influence cortical excitability [1,47]. Metal devices and implants such as patent ductus arteriosus (PDA) clips, ventriculoperitoneal shunts, or mechanical ventilation may also be more common after perinatal brain injury [48]. Such cases may require additional caution, but these medications and devices do not necessarily contraindicate TMS [33,49]. In general, TMS should not be administered to individuals who have ferromagnetic implants in the head, neck, or upper torso (e.g. cochlear implants, programmable shunts) [46]. During TMS, safety assessment can include adapted safety monitoring tools, incorporating caregiver input and infant-specific stress responses [34]. To address the unlikely risk of hearing loss from TMS, age-adequate hearing protection should be ensured [46]. Moldable silicone earplugs are frequently implemented for infant populations. In future research, more detailed reporting of screening procedures, safety assessment, and adverse events, as well as long-term follow-up data, will support increased implementation of TMS in infant populations.

5. Applications of TMS assessment

A limited number of studies to date have implemented TMS as an assessment tool for infants with perinatal brain injury. Early work incorporating TMS in infants has demonstrated changes in motor cortex excitability over the first two years of life, as well as differences in the organization of CST development in infants with brain lesions compared to typically-developing infants [8,13,26].

5.1. Corticospinal development and circuitry

The CST is the primary descending motor pathway that controls voluntary movement. At birth, CSTs are organized bilaterally, descending from each hemisphere to bilateral upper extremities. Around 3–5 months of age, ipsilateral CSTs undergo pruning due to activity-dependent competition, resulting in primarily contralateral control of each limb [50]. However, after damage due to unilateral or asymmetrical perinatal brain injury, the ipsilateral pathways from the non-lesioned hemisphere are sometimes strengthened, while the crossed CST from the lesioned hemisphere may weaken or disappear [26]. About 30–60% of children with unilateral CP will exhibit control over the paretic or more-affected upper extremity from the ipsilateral, non-lesioned hemisphere (ipsilateral circuitry), while the rest maintain some amount of contralateral control from the lesioned hemisphere (contralateral circuitry) [51,52]. Contralateral (typical) circuitry is associated with better response to certain rehabilitation therapies, like constraint-induced movement therapy, and is also associated with better overall motor prognosis and hand function in childhood [53,54]. Corticospinal circuitry therefore shows promise as a potential early predictor of motor outcome and may also guide therapy selection towards therapies best tailored to the individual.

CST pruning and circuitry formation can be assessed in young infants using TMS. Eyre et al. (2007) studied 32 typically-developing infants, 14 neonates with unilateral brain lesions, and 25 neonates with bilateral brain lesions. This study used single-pulse TMS to evaluate cortical excitability at intervals from birth to two years. All children with a unilateral perinatal injury demonstrated contralateral MEPs in response to stimulation of the injured hemisphere at term; approximately half subsequently lost these responses by two years old. In those without injured hemisphere responses, ipsilateral corticospinal projections from the non-lesioned hemisphere were enhanced, with greater excitability, shortened conduction times, and MEP responses in both the ipsilateral and contralateral extremities [26]. Children with ipsilateral circuitry had poorer motor outcomes. Infants with bilateral perinatal lesions had a typical pattern of CST development, though demonstrated higher stimulation thresholds [26,44].

Later work by other teams has also detected MEPs from the lesioned hemisphere of some but not all infants with perinatal brain injury [15,33]. Recent work further investigated the relationship between changes in corticospinal circuitry following perinatal brain injury and later motor outcomes. Kowalski et al (2019) reported on 10 infants with unilateral or asymmetrical perinatal stroke, brain bleed, or periventricular leukomalacia [33]. This study observed MEPs from the more-affected hemisphere more commonly in younger infants (3–6 months corrected age) than older infants (7–12 months corrected age), consistent with prior findings. Atypical movement was observed in 83% of infants with absent MEPs from the more-affected hemisphere, and 25% with present MEPs from the more-affected hemisphere [33].

In addition to circuitry changes, alterations in motor threshold and central motor conduction time have also been observed following perinatal brain injury in comparison to typically-developing infants [26,29,31,44].

5.2. Motor cortex localization and mapping

Motor mapping involves assessing motor cortex representation and localization, with applications for neurosurgery and functional assessment. Narayana et al. (2021) performed upper-extremity motor mapping in 36 patients and lower-extremity motor mapping in 18 patients under the age of 3 [15,37,43]. They observed both intra-hemispheric and inter-hemispheric motor reorganization in many children with a history of perinatal brain injury. They successfully localized upper extremity motor representations in all children in one or both hemispheres; lower extremity motor representations were able to be obtained in most but not all children tested [15]. On average, 14% of stimulations elicited a response. Due to high stimulation thresholds and the potential effect of anti-seizure medications, this study sometimes used CSP to localize the motor cortex instead of MEP. Other studies have also reported more difficulty in assessing lower extremity motor representations in infants with perinatal brain injury. Yang et al. (2013) performed single-pulse and paired-pulse TMS using a double-cone coil in 5 children under 2 years of age to evaluate the effects of intensive exercise training in leg muscles [36]. Children played in a standing position to ensure background contractions. Paired pulses at around ~70% Maximum Stimulator Output (MSO) were more successful at eliciting responses from younger children compared to single pulses, and MEPs were largest when an ISI of 10 ms was used. They noted that MEPs remained difficult to obtain in leg muscles in infants under age 2 years.

In adults, rapid mapping techniques have been found to be feasible and well-tolerated, with some studies showing that reliable motor maps can be obtained in under two minutes [55,56]. Methods to decrease acquisition time for TMS testing would be of benefit in infant populations where tolerance for assessment may be limited. However, factors including infants’ decreased response rate to TMS stimulation and movement during data acquisition would require adaptation of rapid mapping techniques designed for adults. Furthermore, the minimum inter-stimulus interval needed to avoid a lasting neuromodulatory effect has not been defined for infants.

5.3. TMS implications for early detection and intervention in cerebral palsy

Perinatal brain injury is associated with high risk for CP diagnosis. Experts now suggest that a diagnosis of CP can be made prior to 6 months of age using a combination of evidence-based assessments, including movement assessments and neuroimaging, though diagnosis often occurs later [3]. Furthermore, predicting the severity, type (e.g. spastic, ataxic, dyskinetic), and affected body regions (e.g. hemiplegia, diplegia, quadriplegia) of CP at less than two years of age remains difficult. [3] Exploration of other biomarkers for atypical motor development, including through TMS, may advance our current clinical ability to make accurate predictions about CP severity and subtype.

Early detection of CP offers the important advantages of increased referral and access to early intervention during a period characterized by rapid development and potentially heightened neuroplasticity [57,58]. However, without a comprehensive understanding of the unique neural changes and plastic re-organization that occur in the presence of a perinatal brain injury, we lack advanced intervention strategies tailored to each infant’s brain organization and development. As current therapies are often time-, effort-, and cost-intensive [59], identifying treatment strategies most appropriate for each individual’s recovery would reduce existing burden on children, families, and healthcare systems. TMS assessment, as a biomarker for atypical motor system development, could eventually be incorporated into early diagnosis and prognosis paradigms, clarify the optimal period to intervene with rehabilitation and therapies, and guide dosage and effectiveness studies for interventions. As current studies that have implemented TMS as an assessment tool in this population are limited, future research may identify other valuable applications.

6. Conclusions

TMS has demonstrated value as an assessment tool for infants with perinatal brain injury, towards understanding both cortical reorganization and development. Available evidence suggests that, with appropriate screening and monitoring procedures, TMS is feasible and safe in infant populations. TMS can detect alterations in CST organization, conduction, and excitability that are associated with atypical motor function in infants. A more thorough understanding of neurodevelopment and neurophysiology over the first several years of life is needed to maximize the impact of early detection and intervention on developmental outcomes related to perinatal brain injury and CP.

7. Expert Opinion

As we have described, single-pulse TMS allows thorough non-invasive assessment of cortical excitability, corticospinal integrity, and corticospinal circuitry patterns for infants with perinatal brain injury. One of the most promising uses for single-pulse TMS in this population of infants is to identify changes in cortical excitability and/or circuity that provide insight into neuromotor development and potential features of either CP diagnosis or other developmental disability. In adults with stroke, use of TMS to identify MEP presence/absence from the lesioned hemisphere has been included in an algorithm (the ‘PREP’ algorithm) to predict upper-limb function [60]. Such algorithms allow for more accurate determination of prognosis, individualized rehabilitation planning, and stratification of patients in clinical trials [60]. A similar algorithm for infants with perinatal stroke would support early detection and prognosis. Another valuable application for TMS may lie in differentiating responders and non-responders to specific early intervention paradigms, helping to tailor interventions based on individual patterns of development. Though yet unexplored in infants, for older children with CP, TMS assessments of CST circuitry may help identify children most likely to respond to particular rehabilitation interventions [4,53]. More longitudinal research involving infants and young children with perinatal brain injury will help to determine how the development of corticospinal circuitry patterns may vary with age, injury mechanism, and motor function. Future multidisciplinary studies with larger sample sizes, including infants with diverse clinical characteristics, can more fully evaluate the extent to which TMS biomarkers contribute to prediction of CP diagnosis and prognosis. Integrating TMS as a biomarker in intervention trials may identify those children likely to benefit from specific early rehabilitation interventions.

Current challenges to clinical implementation include the early-stage safety profile for TMS in infants, as well as considerable methodological challenges related to acquiring and analyzing TMS data in awake, active infants. Protocols need to accommodate frequent infant movement, which may impact head and coil positioning as well as produce background EMG activity during assessment. While stereotactic neuronavigation allows integration of individual brain anatomy for more accurate targeting, it also requires infant engagement and positioning to ensure the infant is visible to the navigation camera. Personnel must be thoroughly trained to operate TMS and EMG equipment, ensure safety, and maintain infant and caregiver comfort during the procedure. Infant tolerance to TMS procedures varies due to factors such as irritability, sleep/wake cycles, and caregiver comfort. Because of such issues, long assessment protocols (e.g. recruitment curve assessment) may not be feasible. Given the expected variability of infant responses to TMS, multiple assessments across varied age ranges will likely yield the most robust information about individual CST development. Although investigated in adults, no studies have established the reliability of TMS assessment protocols in infant populations or the optimal number of pulses to include in assessment [61,62]. Reliability of TMS assessment protocols in infants may be impacted by less consistent responses to stimulation and increased variability in background muscle activation compared to adults. Future reliability analyses and subsequent optimization of acquisition protocols will therefore be necessary for clinical integration and interpretation of results.

TMS implementation is also limited by the lack of TMS, EMG, and neuronavigation systems designed specifically for infants. Built-in software features for neuronavigation and EMG systems generally require extensive customization to accommodate infant data collection, which may hinder clinical translation. As examples, infant-specific brain templates in neuronavigation systems may be useful in settings where an individual MRI is not available to assist in localizing the motor cortex, and EMG acquisition systems which permit freedom of movement may contribute to infant comfort during testing. In addition, the field of adult TMS is increasingly adopting real-time electric field modeling to understand TMS field strength and spread; however, modeling feasibility in infants is limited by the extensive manual effort required to obtain accurate head model reconstruction in pediatric populations with brain lesions [23]. Infant structural MRI scans are challenging to segment with existing automated algorithms for 3D head modeling due to poor grey-white matter contrast [63]. Future improvements in automating head model reconstruction would be needed for electric field modeling to be routinely implemented.

With the field’s emerging understanding of the timing and process of neuromotor development after early brain injury, we foresee opportunities to intervene in this process to promote improved motor outcomes. Individually-tailored strategies may include the use of traditional rehabilitation therapies or non-invasive neuromodulatory interventions (e.g., rTMS, transcranial direct current stimulation (tDCS), vagal nerve stimulation). In older children with CP, neuromodulation techniques have served as an adjuvant intervention to traditional rehabilitation to facilitate neuroplasticity and motor learning and/or alter interhemispheric inhibition [64,65]. In infants, these tools may offer a means to guide CST development at an early stage of heightened neuroplasticity, promote “directed” sparing or pruning of CSTs, and/or promote activity of penumbral neurons around the area of the brain injury.

In the next ten years, we anticipate that TMS research will result in improved understanding of the individual characteristics impacting cortical excitability and corticospinal circuitry in infants with perinatal brain injury, potentially leading to improved predictors of prognosis and motor outcome. Single-pulse TMS may increasingly make its way into the clinical setting for pediatric populations with perinatal brain injury as a means of understanding neuroplasticity and recovery following injury. We anticipate growth in the area of integrating individualized real-time computational modeling to guide stimulation location and result interpretation, including advancements in neuroimaging analysis tools necessary to perform this modeling in infants. Further, we anticipate emerging research in neuromodulation intervention with expansion into younger age ranges, with the goal of repairing the brain and influencing recovery even earlier for improved outcomes.

Article Highlights:

• Single-pulse TMS assessment in infants with perinatal brain injury has unique methodological considerations related to brain anatomy and administration in awake, moving infants.

• Single-pulse TMS has demonstrated safety in infants with perinatal brain injury, with appropriate screening and safety procedures.

• Motor cortex localization and assessment of motor evoked potentials using TMS is feasible in infants with perinatal brain injury. Higher stimulation levels are typically required, and responses are less consistent than those observed in adults and older children.

• TMS studies in infants with perinatal brain injury have identified changes to corticospinal tract development and integrity over the first two years of life in some infants that may be associated with motor function.

• TMS biomarkers may be useful to inform early diagnosis of cerebral palsy and related rehabilitation therapies; future research in larger sample sizes may more clearly outline the relationship between TMS biomarkers and individual developmental trajectories.