A randomized cross-over study protocol to evaluate long-term gait training with a pediatric robotic exoskeleton outside the clinical setting in children with movement disorders.

Individuals with neuromuscular disorders display a combination of motor control deficits and lower limb weakness contributing to knee extension deficiency characterized by exaggerated stance phase knee flexion. There is a lack of evidence for long-term improvement of knee extension deficiency with currently available clinical treatment programs. Our previous work testing a wearable robotic exoskeleton with precisely timed assistive torque applied at the knee showed immediate increases in knee extension during walking for children with cerebral palsy, which continued to improve over an acute practice period. When we applied interleaved assistance and resistance to knee extension, we observed improvements in knee extension and increased muscle activation indicating the potential for muscle strengthening when used over time. There is a need for additional, high-quality trials to assess the impact of dosage, intensity and volume of training necessary to see persistent improvement in lower limb function for these patient populations. This randomized crossover study (ClinicalTrials.gov: NCT05726591) was designed to determine whether 12 weeks of overground gait training with a robotic exoskeleton outside of the clinical setting, following an initial in clinic accommodation period, has a beneficial effect on walking ability, muscle activity and overall motor function. Participants will be randomized to either complete the exoskeleton intervention or continue their standard therapy for 12 weeks first, followed by a crossover to the other study component. The primary outcome measure is change in peak knee extension angle during walking; secondary outcome measures include gait speed, strength, and validated clinical scales of motor function and mobility. Assessments will be completed before and after the intervention and at 6 weeks post-intervention, and safety and compliance will be monitored throughout. We hypothesize that the 12-week exoskeleton intervention outside the clinical setting will show greater improvements in study outcome measures than the standard therapy.

A call for action: Increasing the pediatric rehabilitation medicine workforce.

Pediatric Rehabilitation Medicine (PRM) is a unique blend of traditional medical rehabilitation knowledge and skills primarily focused on temporary and/or permanent disability conditions of childhood onset throughout the age continuum, with an emphasis on promoting function and participation. Although there are two established pathways to enhance knowledge and skills in PRM, one a combined residency with Pediatrics and the other a PRM fellowship, there has been a relative decline in participants in this training, as has been seen across other subspecialties in Physical Medicine and Rehabilitation (PM&R) and other medical specialties. Based on pediatric rehabilitation physician surveys and the increasing prevalence of children with disabilities, there has been a call to consider opening PRM fellowships to physicians not trained in PM&R. This commentary proposes establishing a commission to lead a transparent and inclusive process to assure that all options to address issues related to optimizing PRM care are considered and provide a course of action to address the needs of children and adults with childhood onset disabilities.

Functional and Structural Brain Connectivity in Children With Bilateral Cerebral Palsy Compared to Age-Related Controls and in Response to Intensive Rapid-Reciprocal Leg Training.

Background: Compared to unilateral cerebral palsy (CP), less is known about brain reorganization and plasticity in bilateral CP especially in relation or response to motor training. The few trials that reported brain imaging results alongside functional outcomes include a handful of studies in unilateral CP, and one pilot trial of three children with bilateral CP. This study is the first locomotor training randomized controlled trial (RCT) in bilateral CP to our knowledge reporting brain imaging outcomes. Methods: Objective was to compare MRI brain volumes, resting state connectivity and white matter integrity using DTI in children with bilateral CP with PVL and preterm birth history (<34 weeks), to age-related controls, and from an RCT of intensive 12 week rapid-reciprocal locomotor training using an elliptical or motor-assisted cycle. We hypothesized that connectivity in CP compared to controls would be greater across sensorimotor-related brain regions and that functional (resting state) and structural (fractional anisotropy) connectivity would improve post intervention. We further anticipated that baseline and post-intervention imaging and functional measures would correlate. Results: Images were acquired with a 3T MRI scanner for 16/27 children with CP in the trial, and 18 controls. No conclusive evidence of training-induced neuroplastic effects were seen. However, analysis of shared variance revealed that greater increases in precentral gyrus connectivity with the thalamus and pons may be associated with larger improvements in the trained device speed. Exploratory analyses also revealed interesting potential relationships between brain integrity and multiple functional outcomes in CP, with functional connectivity between the motor cortex and midbrain showing the strongest potential relationship with mobility. Decreased posterior white matter, corpus callosum and thalamic volumes, and FA in the posterior thalamic radiation were the most prominent group differences with corticospinal tract differences notably not found. Conclusions: Results reinforce the involvement of sensory-related brain areas in bilateral CP. Given the wide individual variability in imaging results and clinical responses to training, a greater focus on neural and other mechanisms related to better or worse outcomes is recommended to enhance rehabilitation results on a patient vs. group level.

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

BACKGROUND: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype. OBJECTIVE: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST. METHODS: This study used a systematic cross-sectional analysis of clinical and molecular features. RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

A scoping review of methods used in musculoskeletal soft tissue and nerve shear wave elastography studies.

This scoping review of shear wave elastography (SWE) articles in musculoskeletal soft tissue and nerve research demonstrates methodological heterogeneity resulting from a lack of standardized data collection and reporting requirements. Seven literature databases were searched for original articles published in English from 2004-2020 that examine human skeletal muscles, tendons, and nerves in vivo. Although 5,868 records were initially identified, only 375 reports met inclusion criteria. Of the 375 articles, 260 examined 89 unique muscles, 94 examined 14 unique tendons, and 43 examined 8 unique nerves. Cohorts were often small (n = 11-20) and young (mean = 20-29 years), and participants were typically tested in the prone position. Regarding equipment, a variety of ultrasound systems (n = 11), ultrasound models (n = 18), and transducers (n = 19) were identified. Only 11% of articles contained information on the use of electromyography to confirm absence of muscle activity, and only 8% reported measurement depth. Since musculoskeletal soft tissue and nerve stiffness can vary significantly based on data collection methods, it is essential to standardize SWE collection and reporting procedures. This will allow SWE to serve as a valid and reproducible tool for assessing tissue pathology, disease progression, and response to intervention within a variety of musculoskeletal and nerve-related disorders.

Adolescents and adults with patellofemoral pain exhibit distinct patellar maltracking patterns.

BACKGROUND: Chronic idiopathic patellofemoral pain is associated with patellar maltracking in both adolescents and adults. To accurately target the underlying, patient-specific etiology, it is crucial we understand if age-of-pain-onset influences maltracking. METHODS: Twenty adolescents (13.9 ± 1.4 years) and 20 adults (28.1 ± 4.9 years) female patients with idiopathic patellofemoral pain (age-of-pain-onset: < 14 and > 18 years of age, respectively) formed the patient cohort. Twenty adolescents and 20 adults (matched for gender, age, and body mass index) formed the control cohort. We captured three-dimensional patellofemoral kinematics during knee flexion-extension using dynamic MRI. Patellar maltracking (deviation in patient-specific patellofemoral kinematics, relative to their respective age-controlled mean values) was the primary outcome measure, which was compared between individuals with adolescent-onset and adult-onset patellofemoral pain using ANOVA and discriminant analysis. FINDINGS: The female adolescent-onset patellofemoral pain cohort demonstrated increased lateral (P = 0.032), superior (P = 0.007), and posterior (P < 0.001) maltracking, with increased patellar flexion (P < 0.001) and medial spin (P = 0.002), relative to the adult-onset patellofemoral pain cohort. Post-hoc analyses revealed increased lateral shift [mean difference ± 95% confidence interval = -2.9 ± 2.1 mm at 10° knee angle], posterior shift [-2.8 ± 2.1 mm, -3.3 ± 2.3 mm & -3.1 ± 2.4 mm at 10°, 20°& 30°], with greater patellar flexion [3.8 ± 2.6 mm & 5.0 ± 2.8 mm, at 20°& 30°] and medial spin [-2.2 ± 1.7 mm & -3.4 ± 2.3 mm at 20°& 30°]. Axial-plane maltracking accurately differentiated the patient age-of-pain-onset (60-75%, P < 0.001). INTERPRETATION: Age-of-pain-onset influences the maltracking patterns seen in patients with patellofemoral pain; with all, but 1, degree of freedom being unique in the adolescent-onset-patellofemoral pain cohort. Clinical awareness of this distinction is crucial for correctly diagnosing a patient's pain etiology and optimizing interventional strategies.

Efficacy and safety of onabotulinumtoxinA with standardized occupational therapy for treatment of pediatric upper limb spasticity: Phase III placebo-controlled randomized trial.

BACKGROUND: This is the first large study of onabotulinumtoxinA as treatment for pediatric upper limb spasticity. OBJECTIVE: Evaluate efficacy and safety of a single treatment with onabotulinumtoxinA plus occupational therapy (OT). METHODS: In this registrational phase III, multinational study (NCT01603602), participants were randomized 1:1:1 to onabotulinumtoxinA 3 U/kg/OT, 6 U/kg/OT, or placebo/OT. Primary endpoint was average change from baseline at weeks 4 and 6 in Modified Ashworth Scale-Bohannon (MAS) score. Secondary endpoints included Modified Tardieu Scale (MTS), Clinical Global Impression of Change (CGI) and functional Goal Attainment Scale (GAS). RESULTS: 235 participants were randomized. At weeks 4 and 6, onabotulinumtoxinA groups had greater mean reductions in MAS (both -1.9; p < 0.001) versus placebo (-1.2). OnabotulinumtoxinA doses improved dynamic tone per MTS. Mean CGI at weeks 4 and 6 was unchanged in the overall population, but improved in a post hoc analysis of patients with a single affected upper limb (UL) muscle group (elbow or wrist). GAS score for passive goals was significantly higher for 6 U/kg versus placebo at week 12. Most AEs were mild/moderate in severity; overall incidence was similar between groups. CONCLUSIONS: OnabotulinumtoxinA (3 and 6 U/kg) was safe and effective in reducing upper limb spasticity in pediatric participants.

Characterizing upper limb function in the context of activities of daily living in CLN3 disease.

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses.

Management of Anterocapitis and Anterocollis: A Novel Ultrasound Guided Approach Combined with Electromyography for Botulinum Toxin Injection of Longus Colli and Longus Capitis.

Chemodenervation of cervical musculature using botulinum neurotoxin (BoNT) is established as the gold standard or treatment of choice for management of Cervical Dystonia (CD). The success of BoNT procedures is measured by improved symptomology while minimizing side effects and is dependent upon many factors including: clinical pattern recognition, identifying contributory muscles, BoNT dosage, and locating and safely injecting target muscles. In patients with CD, treatment of anterocollis (forward flexion of the neck) and anterocaput (anterocapitis) (forward flexion of the head) are inarguably challenging. The longus Colli (LoCol) and longus capitis (LoCap) muscles, two deep cervical spine and head flexor muscles, frequently contribute to these patterns. Localizing and safely injecting these muscles is particularly challenging owing to their deep location and the complex regional anatomy which includes critical neurovascular and other structures. Ultrasound (US) guidance provides direct visualization of the LoCol, LoCap, other cervical muscles and adjacent structures reducing the risks and side effects while improving the clinical outcome of BoNT for these conditions. The addition of electromyography (EMG) provides confirmation of muscle activity within the target muscle. Within this manuscript, we present a technical description of a novel US guided approach (combined with EMG) for BoNT injection into the LoCol and LoCap muscles for the management of anterocollis and anterocaput in patients with CD.

Functional near-infrared spectroscopy to assess sensorimotor cortical activity during hand squeezing and ankle dorsiflexion in individuals with and without bilateral and unilateral cerebral palsy.

Significance: Our study is the first comparison of brain activation patterns during motor tasks across unilateral cerebral palsy (UCP), bilateral cerebral palsy (BCP), and typical development (TD) to elucidate neural mechanisms and inform rehabilitation strategies. Aim: Cortical activation patterns were compared for distal upper and lower extremity tasks in UCP, BCP, and TD using functional near-infrared spectroscopy (fNIRS) and related to functional severity. Approach: Individuals with UCP ( n = 10 , 18.8 ± 6.8 years ), BCP ( n = 14 , 17.5 ± 9.6 years ), and TD ( n = 16 , 17.3 ± 9.1 years ) participated in this cross-sectional cohort study. The fNIRS was used to noninvasively monitor the hemodynamic response to task-related cortical activation. The block design involved repetitive nondominant hand squeezing and ankle dorsiflexion. Results: Individuals with UCP demonstrated the highest levels of activation for the squeeze task ( UCP > BCP q = 0.049 ; BCP > TD q < 0.001 ; and UCP > TD q = 0.001 ) and more activity in the ipsilateral versus contralateral hemisphere. Individuals with BCP showed the highest levels of cortical activation in the dorsiflexion task ( BCP > UCP q < 0.001 ; BCP > TD ). Conclusions: Grouping by CP subtype and manual function or mobility level demonstrated significant differences from TD, even for individuals with the mildest forms of CP. Hemispheric activation patterns showed hypothesized but nonsignificant trends.

Utility and practice of electrodiagnostic testing in the pediatric population: An AANEM consensus statement.

Nerve conduction studies and needle electromyography, collectively known as electrodiagnostic (EDX) studies, have been available for pediatric patients for decades, but the accessibility of this diagnostic modality and the approach to testing vary significantly depending on the physician and institution. The maturation of molecular diagnostic approaches and other diagnostic technologies such as neuromuscular ultrasound indicate that an analysis of current needs and practices for EDX studies in the pediatric population is warranted. The American Association of Neuromuscular & Electrodiagnostic Medicine convened a consensus panel to perform literature searches, share collective experiences, and develop a consensus statement. The panel found that electrodiagnostic studies continue to have high utility for the diagnosis of numerous childhood neuromuscular disorders, and that standardized approaches along with the use of high-quality reference values are important to maximize the diagnostic yield of these tests in infants, children, and adolescents.

Reply to Comment on Ultrasound Guidance for Botulinum Neurotoxin Chemodenervation Procedures. Toxins 2018, 10, 18-Quintessential Use of Ultrasound Guidance for Botulinum Toxin Injections.

We thank the authors for their detailed letter and salient comments related to our article on Ultrasound Guidance for botulinum toxin (BoNT) injections.[...].

Indications for neuromuscular ultrasound: Expert opinion and review of the literature.

Over the last two decades, dozens of applications have emerged for ultrasonography in neuromuscular disorders. We wanted to measure its impact on practice in laboratories where the technique is in frequent use. After identifying experts in neuromuscular ultrasound and electrodiagnosis, we assessed their use of ultrasonography for different indications and their expectations for its future evolution. We then identified the earliest papers to provide convincing evidence of the utility of ultrasound for particular indications and analyzed the relationship of their date of publication with expert usage. We found that experts use ultrasonography often for inflammatory, hereditary, traumatic, compressive and neoplastic neuropathies, and somewhat less often for neuronopathies and myopathies. Usage significantly correlated with the timing of key publications in the field. We review these findings and the extensive evidence supporting the value of neuromuscular ultrasound. Advancement of the field of clinical neurophysiology depends on widespread translation of these findings.

Relationship between sensorimotor cortical activation as assessed by functional near infrared spectroscopy and lower extremity motor coordination in bilateral cerebral palsy.

Background: Evaluation of task-evoked cortical responses during movement has been limited in individuals with bilateral cerebral palsy (CP), despite documented alterations in brain structure/function and deficits in motor control. Objective: To systematically evaluate cortical activity associated with lower extremity tasks, and relate activation parameters to clinical measures in CP. Methods: 28 ambulatory participants (14 with bilateral CP and 14 with typical development) completed five motor tasks (non-dominant ankle dorsiflexion, hip flexion and leg cycling as well as bilateral dorsiflexion and cycling) in a block design while their sensorimotor cortex was monitored using functional near infrared spectroscopy (fNIRS), in addition to laboratory and clinical measures of performance. Results: Main effects for group and task were found for extent of fNIRS activation (number of active channels; p < 0.001 and p = 0.010, respectively), magnitude of activation (sum of beta values; p < 0.001 for both), and number of active muscles (p = 0.001 and p < 0.001, respectively), but no group by task interactions. Collectively, subgroups with CP and especially those with greater impairments, showed higher extent and magnitude of cortical sensorimotor activation as well as higher amounts of concurrent activity in muscles not required for task performance. Magnitude of fNIRS activation during non-dominant dorsiflexion correlated with validated measures of selective control (r = -0.60, p = 0.03), as well as mobility and daily activity (r = -0.55, p = 0.04 and r = -0.52, p = 0.05, respectively) and self-reported gait function (r = -0.68, p = 0.01) in those with CP. Conclusions: The association between higher activity in the sensorimotor cortex and decreased selectivity in cortical organization suggests a potential neural mechanism of motor deficits and target for intervention.

Regional Rheumatic Disorders and Rehabilitation in Older Adults: An Update.

Musculoskeletal problems are the most frequently reported complaints among older adults living in the community. The impact of the aging process on skeletal muscles and joints can have a profound effect on the ability of individuals to function. This article reviews the rehabilitation medicine approach to the evaluation of older adults with regional rheumatic disorders and the rehabilitation medicine considerations for clinical intervention. Future research is required to gain a greater understanding of the subject matter and its impact on the provision of care and patients' quality of life.

Ultrasound Guidance for Botulinum Neurotoxin Chemodenervation Procedures.

Injections of botulinum neurotoxins (BoNTs) are prescribed by clinicians for a variety of disorders that cause over-activity of muscles; glands; pain and other structures. Accurately targeting the structure for injection is one of the principle goals when performing BoNTs procedures. Traditionally; injections have been guided by anatomic landmarks; palpation; range of motion; electromyography or electrical stimulation. Ultrasound (US) based imaging based guidance overcomes some of the limitations of traditional techniques. US and/or US combined with traditional guidance techniques is utilized and or recommended by many expert clinicians; authors and in practice guidelines by professional academies. This article reviews the advantages and disadvantages of available guidance techniques including US as well as technical aspects of US guidance and a focused literature review related to US guidance for chemodenervation procedures including BoNTs injection.

Shoulder muscle atrophy and its relation to strength loss in obstetrical brachial plexus palsy.

BACKGROUND: Treatment/prevention of shoulder muscle strength imbalances are major therapeutic goals for children with obstetrical brachial plexus palsy. The study aims were to characterize muscle atrophy in children/adolescents with unilateral obstetrical brachial plexus palsy, to quantify the agonist-antagonist muscle volume balance and the association between muscle volume and strength. METHODS: Eight boys and four girls (age=12.1, standard deviation=3.3) participated in this case-control study. Three-dimensional magnetic resonance images of both shoulders were acquired. The unimpaired shoulder served as a reference. Volumes of deltoid, pectoralis major, supraspinatus, infraspinatus, teres major, subscapularis were calculated based on 3D models, derived through image segmentation. Maximal isometric torques were collected in six directions. FINDINGS: All the major muscles studied were significantly atrophied. The teres major demonstrated the biggest difference in atrophy between groups (51 percentage points), the pectoralis major was the least atrophied (23 percentage points). The muscle volume distribution was significantly different between shoulders. Muscle volume could predict maximal voluntary isometric torques, but the regression coefficients were weaker on the impaired side (72% to 91% of the strength could be predicted in the uninvolved side and 24% to 90% in the involved side and external rotation strength could not be predicted). INTERPRETATION: This study demonstrates muscle atrophy varied across all the main shoulder muscles of the glenohumeral joint, leading to significant muscle volume imbalances. The weaker coefficients of determination on the impaired side suggest that other variables may contribute to the loss of strength in addition to atrophy.

Task-Specific and Functional Effects of Speed-Focused Elliptical or Motor-Assisted Cycle Training in Children With Bilateral Cerebral Palsy: Randomized Clinical Trial.

BACKGROUND: Locomotor training using treadmills or robotic devices is commonly utilized to improve gait in cerebral palsy (CP); however, effects are inconsistent and fail to exceed those of equally intense alternatives. Possible limitations of existing devices include fixed nonvariable rhythm and too much limb or body weight assistance. OBJECTIVE: To quantify and compare effectiveness of a motor-assisted cycle and a novel alternative, an elliptical, in CP to improve interlimb reciprocal coordination through intensive speed-focused leg training. METHODS: A total of 27 children with bilateral CP, 5 to 17 years old, were randomized to 12 weeks of 20 minutes, 5 days per week home-based training (elliptical = 14; cycle = 13) at a minimum of 40 revolutions per minute, with resistance added when speed target was achieved. Primary outcomes were self-selected and fastest voluntary cadence on the devices and gait speed. Secondary outcomes included knee muscle strength, and selective control and functional mobility measures. RESULTS: Cadence on trained but not nontrained devices increased, demonstrating task specificity of training and increased exercise capability. Mean gait speed did not increase in either group, nor did parent-reported functional mobility. Knee extensor strength increased in both. An interaction between group and time was seen in selective control with scores slightly increasing for the elliptical and decreasing for the cycle, possibly related to tighter limb coupling with cycling. CONCLUSIONS: Task-specific effects were similarly positive across groups, but no transfer was seen to gait or function. Training dose was low (≤20 hours) compared with intensive upper-limb training recommendations and may be insufficient to produce appreciable clinical change.

Spasticity Video Challenge: A Look at Methods for Addressing Difficult Cases.

As seen in this CME online activity (available at http://courses.elseviercme.com/spasticity/662e), treatment of patients with spasticity due to upper motor neuron syndromes, including traumatic brain injury, stroke, and cerebral palsy, is multifaceted, involving chemodenervation, systemic medications, surgical therapy, rehabilitation efforts, and home care. Optimal care begins with the recognition that each patient's impairments are unique and must be assessed carefully to determine the impact of muscle overactivity, loss of dexterity, and weakness on passive and active function in the context of the patients' goals. While botulinum toxin plays a major role in providing symptomatic relief and functional improvement from hypertonia, it should rarely be used as a standalone treatment.

Hearing Safety From Single- and Double-Pulse Transcranial Magnetic Stimulation in Children and Young Adults.

PURPOSE: Concerns regarding hearing safety have limited the number of studies using transcranial magnetic stimulation (TMS) in children and young adults. The objective of this study was to examine the safety of TMS with regards to hearing in a group of 16 children and young adults (17.3 ± 4.9 years) with and without brain injury. METHODS: Pure-tone hearing thresholds and distortion-product otoacoustic emissions were measured before and after exposure to single- and paired-pulse TMS (1-2 sessions of 149-446 TMS pulses at a median of 49%-100% maximum stimulator output over a 2.2 hours period). RESULTS: No mean change in hearing outcomes was noted. In addition, no clinically significant change in hearing threshold was observed in any participant, and participants did not experience a subjective change in hearing after TMS exposure. CONCLUSIONS: Single- and double-pulse TMS administered within the parameters used in this study, which included hearing protection, can be used in children and young adults without impacting hearing. This study provides further evidence for hearing safety after TMS exposure in children and young adults.